BEACON: A Phase II, Patient-blinded, Two-part, Randomized, Parallel-group Trial to Evaluate the Safety, Tolerability, Pharmacokinetics, and Efficacy of LYR-220 in Chronic Rhinosinusitis (CRS) Patients Who Have Had a Prior Ethmoidectomy
Phase: PHASE2
Conditions: Chronic Sinusitis, Chronic Rhinosinusitis (Diagnosis)
Sponsor: Lyra Therapeutics

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CLINICAL STUDY PROTOCOL 
Protocol Number: LYR-220-2021-001 
Study Title: BEACON: A Phase II, Patient-blinded, Two-part, 
Randomized, Parallel-group Trial to Evaluate the Safety, 
Tolerability, Pharmacokinetics, and Efficacy of LYR-220 
in Chronic Rhinosinusitis (CRS) Patients Who Have Had a 
Prior Ethmoidectomy  
Version:  4.0 
Effective Date: 30 August 2022 
NCT# NCT05035654 
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. 

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SPONSOR SIGNATURE PAGE 
Protocol Number: LYR-220-2021-001 
Study Title: BEACON: A Phase II, Patient-blinded, Two-part, Randomized, 
Parallel-group Trial to Evaluate the Safety, Tolerability, 
Pharmacokinetics, and Efficacy of LYR-220 in Chronic 
Rhinosinusitis (CRS) Patients Who Have Had a Prior 
Ethmoidectomy 
Sponsor: Lyra Therapeutics, Inc. 
480 Arsenal Way 
Watertown, MA USA 02472 
Version: 4.0 
Signed:  
Signed:  

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COORDINATING INVESTIGATOR SIGNATURE PAGE 
Protocol Number: LYR-220-2021-001 
Study Title: BEACON: A Phase II, Patient-blinded, Two-part, Randomized, 
Parallel-group Trial to Evaluate the Safety, Tolerability, 
Pharmacokinetics, and Efficacy of LYR-220 in Chronic 
Rhinosinusitis (CRS) Patients Who Have Had a Prior 
Ethmoidectomy 
Sponsor: Lyra Therapeutics, Inc. 
480 Arsenal Way 
Watertown, MA USA 02472 
Version: 4.0 
Signed:  
Brent Senior, M.D. 
Coordinating Investigator 
Date:  
            (DDMMMYYYY) 

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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. 
If 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 (CV) along with the current 
CV of those physicians at this institution who will be using this investigational product or 
participating in this study as Subinvestigators 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. 
Investigator:  
Name (Print): _________________________________________________________________  
Signature: _____________________________ 
Date of Signature: ___________________ 
 
(DD MMM YYYY) 
Site Number: __________________________ 
 
 

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TABLE OF CONTENTS 
 
SPONSOR SIGNATURE PAGE ..................................................................................................2 
COORDINATING INVESTIGATOR SIGNATURE PAGE ....................................................3 
INVESTIGATOR AGREEMENT SIGNATURE PAGE ..........................................................4 
TABLE OF CONTENTS ..............................................................................................................5 
LIST OF TABLES .........................................................................................................................7 
LIST OF FIGURES .......................................................................................................................7 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ...............................................8 
1. 
SYNOPSIS ............................................................................................................................10 
2. 
INTRODUCTION ................................................................................................................23 
2.1 
Chronic Rhinosinusitis ...............................................................................................23 
2.2 
Product Rationale .......................................................................................................24 
2.3 
Study Rationale ..........................................................................................................25 
3. 
STUDY OBJECTIVES AND ENDPOINTS ......................................................................26 
4. 
INVESTIGATIONAL PLAN ..............................................................................................29 
4.1 
Overall Study Design .................................................................................................29 
4.1.1 
Screening and Run-in Stage .....................................................................30 
4.1.2 
Treatment Stage ........................................................................................30 
4.1.3 
Post-treatment Follow-Up Stage ..............................................................31 
4.1.4 
End of the Trial .........................................................................................31 
4.2 
Rationale for Study Design ........................................................................................32 
4.3 
Discontinuation of Study Subjects .............................................................................32 
4.4 
Criteria for Study Termination ...................................................................................33 
5. 
SELECTION OF SUBJECTS .............................................................................................34 
5.1 
Subject Screening .......................................................................................................34 
5.2 
Subject Informed Consent ..........................................................................................34 
5.3 
Inclusion Criteria ........................................................................................................34 
5.4 
Exclusion Criteria .......................................................................................................35 
6. 
TREATMENT OF SUBJECTS ..........................................................................................38 
6.1 
Subject Allocation ......................................................................................................38 
6.1.1 
Enrollment ................................................................................................38 
6.1.2 
Randomization (Part 2 Study Only) .........................................................38 
6.2 
Study Product Administration ....................................................................................38 
6.2.1 
Pre-procedure Medication ........................................................................38 
6.2.2 
Study Product Preparation ........................................................................38 
6.2.3 
Study Product Administration ..................................................................38 
6.2.4 
Enrollment Failure ....................................................................................39 
6.2.5 
End of Day 1 Visit ....................................................................................39 
6.3 
Blinding ......................................................................................................................39 
6.3.1 
Procedures for Breaking the Blind Prior to Study Completion ................39 
6.4 
Prior and Concomitant Medications ...........................................................................40 
6.4.1 
Prior Medications .....................................................................................40 
6.4.2 
Prohibited Concomitant Medications .......................................................40 
6.4.3 
Permitted Concomitant Medications ........................................................40 
6.4.4 
Rescue Concomitant Medications and Treatment ....................................41 

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6.5 
Removal Procedure ....................................................................................................41 
6.6 
Treatment Compliance ...............................................................................................42 
7. 
DRUG PRODUCT MATERIALS AND MANAGEMENT .............................................43 
7.1 
Investigational Product ...............................................................................................43 
7.1.1 
Product Description ..................................................................................43 
7.1.2 
Dosage and Administration ......................................................................43 
7.2 
Drug Product Management ........................................................................................44 
7.2.1 
Packaging and Labeling ...........................................................................44 
7.2.2 
Storage ......................................................................................................44 
7.2.3 
Product Traceability .................................................................................45 
7.2.4 
Product Accountability .............................................................................45 
7.2.5 
Product Return ..........................................................................................45 
8. 
STUDY ASSESSMENTS .....................................................................................................46 
8.1 
Study Schedule of Assessment ...................................................................................46 
8.2 
Assessment of Subject Characteristics .......................................................................50 
8.2.1 
Demographics ...........................................................................................50 
8.2.2 
Medical and Surgical History ...................................................................50 
8.3 
Assessment of Safety ..................................................................................................50 
8.3.1 
Physical Examination ...............................................................................50 
8.3.2 
Vital Signs ................................................................................................50 
8.3.3 
Laboratory Assessments ...........................................................................51 
8.3.4 
Nasal Endoscopy Assessments .................................................................51 
8.3.5 
Ophthalmologic Assessments ...................................................................52 
8.3.6 
SCS rescue ................................................................................................52 
8.3.7 
Sinonasal surgery (actual or planned) for CRS ........................................52 
8.3.8 
Pharmacokinetic Analysis ........................................................................53 
8.3.9 
Explanted LYR-220 Analysis ..................................................................53 
8.3.10 
Pregnancy or Breast Feeding ....................................................................53 
8.3.11 
Adverse Events and Serious Adverse Events ...........................................54 
8.3.12 
Safety Monitoring .....................................................................................58 
8.4 
Assessment of Efficacy ..............................................................................................59 
8.4.1 
Subject Reported Outcomes .....................................................................59 
8.4.2 
Ethmoid Cavity Opacification Imaging ...................................................61 
8.4.3 
Nasal Inflammatory Marker Levels .........................................................61 
9. 
STATISTICAL ANALYSIS ................................................................................................62 
9.1 
Sample Size ................................................................................................................62 
9.2 
Analysis Populations ..................................................................................................62 
9.3 
Disposition and Population Assignment ....................................................................62 
9.4 
Demographic and Other Baseline Characteristics ......................................................62 
9.5 
Prior and Concomitant Medications ...........................................................................62 
9.6 
Safety Analyses ..........................................................................................................63 
9.7 
Pharmacokinetic Analyses .........................................................................................63 
9.7.1 
Pharmacokinetic Concentrations ..............................................................63 
9.7.2 
Pharmacokinetic Parameters ....................................................................63 
9.8 
Efficacy Analyses .......................................................................................................64 
9.8.1 
Efficacy Endpoint Analysis ......................................................................64 

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9.9 
Interim Analysis/ Study Adaptation ...........................................................................65 
10. REGULATORY OBLIGATIONS ......................................................................................66 
10.1 
Statements of Compliance ..........................................................................................66 
10.2 
Site Selection and Training ........................................................................................66 
10.3 
Ethics Committee (EC) or Institutional Review Board (IRB) Approval ...................66 
10.4 
Informed Consent .......................................................................................................67 
10.5 
Protocol Amendments ................................................................................................68 
10.6 
Protocol Deviations ....................................................................................................68 
10.7 
Study Monitoring .......................................................................................................69 
10.8 
Data Quality Assurance ..............................................................................................69 
10.9 
Record Retention ........................................................................................................70 
10.10 Auditing 70 
10.11 Use and Publication of Study Results ........................................................................70 
10.12 Confidentiality ............................................................................................................71 
10.13 Early Study Discontinuation ......................................................................................71 
11. CLINICAL RISK AND BENEFIT ANALYSIS ................................................................73 
12. LIST OF REFERENCES ....................................................................................................77 
13. APPENDICES ......................................................................................................................81 
13.1 
CRS Cardinal Symptoms (CS) Questionnaire (Daily ePRO) [SAMPLE] .................82 
13.2 
22-Item Sino-Nasal Outcome Test (SNOT-22) [SAMPLE] ......................................84
13.3 
Patient-Reported Outcome Measure for Chronic Rhinosinusitis (CRS-
PRO) Questionnaire [SAMPLE] ................................................................................85 
13.4 
Patient Global Impression of Severity (PGIS) Scale [SAMPLE] ..............................86 
13.5 
Patient Global Impression of Change (PGIC) Scale [SAMPLE] ...............................87 
13.6 
LYR-220 End-of-Study Questionnaire [SAMPLE] ...................................................88 
13.7 
Summary of Protocol Changes ...................................................................................91 
LIST OF TABLES 
Table 1: Schedule of Assessments for Subjects Enrolled ..............................................................48 
Table 2: Categorized Survey Items for Separate Domains of the SNOT-22 Instrument...............60 
LIST OF FIGURES 
Figure 1: Study Design Schematic .................................................................................................29 
Figure 2: Images of the Two LYR-220 Drug Matrices .................................................................43 
Figure 3: LYR-220 Applicator Packaged with Drug Matrix (A) and Sham Applicator (B)  ........44 

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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
Abbreviation / Term 
Definition 
AE 
Adverse event 
AR 
Allergic rhinitis (seasonal or perennial) 
ARS 
American Rhinologic Society 
ANCOVA 
Analysis of covariance 
CFBL 
Change from baseline 
CFR 
Code of Federal Regulations 
CI 
Confidence interval 
CMH 
Cochran-Mantel-Haenszel 
COPD 
Chronic obstructive pulmonary disorder 
CRF 
Case report form 
CRO 
Contract research organization 
CRS 
Chronic rhinosinusitis 
CRS-PRO 
Patient-reported outcome measure for chronic rhinosinusitis 
CS 
Cardinal symptoms of CRS 
CT 
Computed tomography 
CTRA 
Clinical trial research agreement 
CV 
Curriculum vitae 
CYP3A4 
Cytochrome P-450 3A4 
EC 
Ethics Committee  
EDC 
Electronic data capture 
EOS 
End-of-study 
EOT 
End-of-treatment 
ePRO 
Electronic patient-reported outcome 
ET 
Early termination 
FDA 
Food and Drug Administration 
FSH 
Follicle stimulating hormone 
FESS 
Functional endoscopic sinus surgery 
GCP 
Good clinical practice 
HEENT 
Head, ears, eyes, nose, and throat  
IB 
Investigator’s brochure 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IFU 
Instructions for use 
IgA 
Immunoglobulin A 
IgG 
Immunoglobulin G 
INCS 
Intranasal corticosteroid spray 
IOP 
Intraocular pressure 
IRB 
Institutional Review Board 

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Abbreviation / Term 
Definition 
IRT 
Interactive Response Technology 
IUD 
Intrauterine device 
IUS 
Intrauterine hormone-releasing system 
kg 
kilogram 
K-M
Kaplan-Meier 
LOCF
Last observation carried forward 
μg
microgram 
MedDRA
Medical Dictionary for Regulatory Activities 
MF
Mometasone furoate 
mg
milligram 
mL
milliliter 
mm Hg
Millimeters of mercury 
MMP
Medical monitoring plan 
MMRM
Mixed model of repeated measures 
mRNA
Messenger ribonucleic acid 
NSAID
Nonsteroidal anti-inflammatory drug 
pg
picogram 
PGIC
Patient Global Impression of Change 
PGIS
Patient Global Impression of Severity 
PK
Pharmacokinetics 
SAE
Serious adverse event 
SAR
Seasonal allergic rhinitis 
SCS
Systemic corticosteroid 
SD
Standard deviation 
SNOT-22
Sino-Nasal Outcome Test (22-item) 
SOP
Standard operating procedure 
SUSAR
Serious unexpected suspected adverse reaction 
TEAE
Treatment-emergent adverse event 
TESAE
Treatment-emergent serious adverse event 
UADE
Unexpected adverse device effect 
URTI
Upper respiratory tract infection 
US
United States 

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1. 
SYNOPSIS 
Sponsor  Lyra Therapeutics, Inc. 
480 Arsenal Way 
Watertown, MA 02472, USA 
Protocol Title  
 
BEACON: A Phase II, Patient-blinded, Two-part, 
Randomized, Parallel-group Trial to Evaluate the Safety, 
Tolerability, Pharmacokinetics, and Efficacy of LYR-220 in 
Chronic Rhinosinusitis (CRS) Patients Who Have Had a 
Prior Ethmoidectomy 
Protocol Number  LYR-220-2021-001  
Phase of Development Phase II 
Investigational Product LYR-220-32 System (7500 μg) and LYR-220-16 System 
(7500 μg) 
Active Ingredient Mometasone furoate (MF) 
Trial Location Worldwide 
Number of Sites  Up to 25 sites  
Study Population  Adult CRS patients who have had a prior bilateral total 
ethmoidectomy 
Estimated Number of Subjects Approximately 50 subjects  
Study Endpoints 
Primary  
- Product-related unexpected serious adverse events 
Pharmacokinetics 
- Plasma MF concentrations at 1 hour post study treatment administration and at Days 2 or 3, 
Days 5 or 8, and Weeks 4, 12, 16 or 20, 24, and 25 
Secondary – Safety 
- Treatment-emergent adverse events (TEAEs) and serious adverse events (TESAEs) through 
Week 28 
- Clinically significant abnormal laboratory values (hematology and chemistry) through Week 
25 
- Newly identified or worsened endoscopic findings (epistaxis and mucosal injury) in ethmoid 
cavity through Week 25 

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- Clinically significant increase of IOP through Week 25 
A clinically significant increase of IOP is defined as IOP in 1 or both eyes >23 mm Hg or an 
increase of IOP from Baseline in 1 or both eyes 10 mm Hg. 
- Newly identified or worsened cataract in 1 or both eyes by slit-lamp examination through 
Week 25 
Secondary – Efficacy 
- Change from baseline (CFBL) in SNOT-22 total and subdomain scores at Weeks 2, 4, 6, 8, 
12, 16, 20, 24, and 28 
The SNOT-22 questionnaire is a 22-item disease-specific quality of life instrument validated 
for use in CRS. Each symptom is scored as it has been over the past 2 weeks on a 6-point 
scale as follows: 0 = no problem, 1 = very mild problem, 2 = mild or slight problem, 3 = 
moderate problem, 4 = severe problem, 5 = problem as bad as it can be. 
- CFBL in the average composite score over the preceding 7 days of 3 cardinal symptoms 
(3CS) and individual cardinal symptom scores at Weeks 2, 4, 6, 8, 12, 16, 20, 24, and 28 
The 3 cardinal symptoms include nasal blockage/obstruction/congestion, facial pain/ 
pressure, 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. 
- CFBL in average loss of smell score over the preceding 7 days for all subjects and for 
VXEMHFWVZLWKEDVHOLQHVFRUH at Weeks 2, 4, 6, 8, 12, 16, 20, 24, and 28 
- Change from baseline (CFBL) in Patient-Reported Outcome Measure for Chronic 
Rhinosinusitis (CRS-PRO) total and subdomain scores at Day 8 and Weeks 2, 3, 4, 6, 8, 12, 
16, 20, 24, and 28 
The CRS-PRO questionnaire is a 12-item disease-specific health-related impairment for use 
in CRS. Each symptom is scored as it has been over the past 7 days on a 5-point scale as 
follows: 0 = not at all, 1 = a little bit, 2 = somewhat, 3 = quite a bit, 4 = very much. 
- Time to first use of rescue treatment recommendation through Week 28 
Rescue treatment is defined as, after subject enrollment, worsening or acute exacerbation of 
CRS in a subject resulting in the treating physician reporting an escalation of treatment, 
including systemic corticosteroids (SCS) and/or sinonasal surgery. Rescue treatment is not 
recommended if worsening of symptoms is less than 3 days duration.  
- Oral steroids use or sinonasal surgery through Week 28 
- CFBL in bilateral percent ethmoid cavity opacification by CT at Week 25 
- CFBL in Patient Global Impression of Severity (PGIS) score at Weeks 8, 16, and 24 
- Patient Global Impression of Change (PGIC) score at Week 24 

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- No longer a candidate for revision surgery 
Subjects will be deemed as having converted if they do not undergo revision sinonasal 
surgery (planned or actual) during the study and if they meet the following criteria: 
x 3CS score 4 at Week 24, or 
x No disease in ethmoid cavities on Week 25 CT  
- CFBL in nasal inflammatory marker levels at Week 25 
Study Design 
This multicenter study will be conducted in a patient-blinded, two-part, randomized, parallel-
group manner in approximately 50 symptomatic adult subjects with CRS who have had a prior 
bilateral ethmoidectomy. The safety, tolerability, pharmacokinetics, and efficacy of 2 designs, 
LYR-220-32 drug matrix and LYR-220-16 drug matrix, will be assessed. Both designs of 
LYR-220 matrices contain 7500 μg of the corticosteroid mometasone furoate (MF). 
The study will consist of 2 parts. In part 1 of the study, up to 10 subjects will be treated with 
either design of LYR-220 bilaterally. The primary objective of the part 1 study, in addition to 
the safety and pharmacokinetics assessments of LYR-220, is to evaluate the feasibility of 
placement and optimize the LYR-220 insertion procedure before beginning part 2 of the study, 
in which approximately 40 subjects will be randomized 1:1to treatment with LYR-220-32 
(7500 ug) or to a sham treatment. 
Each subject will undergo 3 stages during the study:  
x Screening and Run-in Stage: 2-4 weeks  
x Treatment Stage: 24 weeks  
x Post-treatment Follow-Up Stage: 4 weeks 
Screening and Run-in 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 2–4-week run-in period. During this run-in period, except for a background 
therapy of daily saline irrigation, subjects will receive no other active treatment for CRS or any 
prohibited or rescue medications specified in the study protocol. Beginning at least 14 days 
prior to LYR-220 insertion procedure on Treatment Day (Day 1), subjects will record daily 
cardinal symptoms (CS) of CRS on the electronic patient-reported outcomes (ePRO) system. 
At Screening, the SNOT-22 and CRS-PRO will also be collected. 
Treatment Stage 
The total duration of the Treatment Stage will be approximately 24 weeks.  
In part 1 of the study, on Day 1, subjects will be treated with any design of LYR-220 
bilaterally. The LYR-220 insertion procedure will be assessed and optimized, if necessary, 
before the randomized part 2 stage.  

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In part 2 of the study, on Day 1, before any treatment, subjects will be randomized in a 1:1ratio 
to 1 of the 2 study arms:  
x Treatment Arm A: bilateral insertion of LYR-220-32 (7500 μg)  
x Treatment Arm B: bilateral sham procedure 
Subjects in part 2 of the study will be stratified for treatment assignment according to the 
following criteria: 
x Nasal polyps (Yes vs No) 
No more than 10 subjects with polyps will be enrolled in each treatment arm 
Subjects enrolled in either part of the study will undergo the same study procedures and 
assessments. On Day 1, after completing any required pretreatment baseline assessments, 
subjects will receive local anesthetic and may receive decongestants in the ethmoid cavity for 
endoscopic assessment and in preparation for the insertion procedure.  
All subjects will return to clinic for the scheduled follow-up assessments at Day 2 or 3, Day 5 
or 8, and Week 4, Week 12, Week 16 or 20, and Week 24 visits. Subjects will receive 
telephone follow-ups at Week 8 and Week 16 or 20 (ie, the week they are not scheduled to 
attend in-clinic visit for PK blood draw) 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 have been treated with LYR-220 will have the bilateral matrices 
removed using standard surgical tools and control group subjects will undergo a sham removal 
procedure. 
If spontaneous dislodgement of LYR-220 occurs before the scheduled Week 24/EOT visit, 
subjects are required to call the study clinic immediately to report the event. If a subject 
experiences dislodgement of 1 of the bilateral matrices, the subject will continue in the 
treatment phase unless an early treatment discontinuation is recommended by the treating 
physician or subject requests matrix removal from the remaining side of the nose. If matrices 
spontaneously dislodge from both sides of the nose, the subject will complete an Unscheduled 
early-termination (ET) visit within 7 days of the second matrix dislodgement, and complete 
the assessments scheduled for the Week 24/EOT visit. Spontaneously dislodged LYR-220 
should be retained, if available, and returned to the clinic at subject’s next visit. 
If medically warranted, according to the treating physician’s discretion (for example, needing 
sinonasal surgery as rescue treatment), early matrix removal may be performed at an 
unscheduled ET visit.  
Any subject who undergoes an ET visit is required to complete the assessments scheduled for 
the Week 24/EOT visit and should stay in the study and complete the assessments scheduled 
for the Week 25 visit within 5-9 days after the ET visit.  
Post-treatment Follow-Up Stage 

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All subjects will undergo a 1-week post-treatment follow-up visit (Week 25 visit). AEs, 
concomitant medications/procedures, endoscopy, nasal swabs, ophthalmologic assessments, 
CT, and other scheduled assessments will be performed at the Week 25 visit. In addition, 
subjects will complete a 4-week post-treatment follow-up by telephone or in-clinic visit [Week 
28/end-of-study (EOS)]. End of study assessments include AEs, concomitant 
medications/procedures, and final ePROs (4CS, SNOT-22, CRS-PRO, and End-of-Study 
Questionnaire). 
Assessments 
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.  
Routine safety assessments will be performed during the screening visit including vital signs 
and limited physical exams of head, eyes, ears, nose, and throat (HEENT). Samples for 
hematology and chemistry will be collected at Screening and Week 25 visits.  
Nasal cavities will be assessed by endoscopy at Screening, on Day 1 before the LYR-220 
insertion procedure, and at Week 4, 12, 24/EOT (before LYR-220 removal), and Week 25 
visits. Local safety evaluation of the ethmoid cavity will be performed at these visits to 
document presence of epistaxis, mucosal injury, and any other local adverse effects. On Day 1 
(before LYR-220 insertion) and at Week 25 visits, nasal swabs will be collected in the ethmoid 
cavities to evaluate the impact of LYR-220 on nasal inflammatory marker levels by protein and 
mRNA assays.  
Ophthalmologic assessments will include IOP and slit-lamp examination during Screening and 
at Week 25 visit. IOP assessment will also be performed at Week 4 and 12 visits. 
For female subjects of childbearing potential, a serum pregnancy test will be performed at the 
Screening visit and a urine pregnancy test will be performed on Day 1 prior to treatment to 
confirm eligibility for participating in the study. Additionally, a urine pregnancy test will be 
performed at Weeks 4, 12, and 24/EOT or ET visits in these female subjects. 
Plasma samples for PK will be collected from all subjects on 9 occasions: 
x Day 1 pre-procedure 
x 1 hour (±10 min) post procedure on Day 1 
x Day 2 or 3* 
x Day 5 or 8* 
x Week 4 
x Week 12 

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x Week 16 or 20* 
x Week 24/EOT 
x Week 25 
[*Note: Subjects will be asked to come to the clinic on either one of the 2 visit options.] 
Enrolled subjects will be asked to complete a daily ePRO questionnaire to assess the severity of 
the 4 cardinal symptoms (CS) of CRS including nasal blockage/obstruction/congestion, facial 
pain/pressure, anterior/posterior nasal discharge, and loss of smell. In addition, the ePRO will 
capture use of daily saline irrigation by the subjects. Subjects will also complete 2 validated 
CRS-specific quality of life questionnaires, the SNOT-22 and CRS-PRO, at Screening, on Day 
1 before treatment, and at Weeks 2, 4, 6, 8, 12, 16, and 20, at Week 24 before matrix removal, 
and at Week 28/EOS. CRS-PRO will also be assessed at Day 8 and Week 3. The PGIS will be 
assessed at Day 1 and at Weeks 8, 16, and 24/EOT. The PGIC will be assessed at Week 
24/EOT. At Week 28/EOS visit, an End-of-Study questionnaire will be administered.  
Ethmoid cavity opacification will be assessed by CT scans obtained during Screening (or using 
a historical CT scan taken within 3 months of Screening) and at Week 25 visit, unless 
medically contraindicated. Subjects will be instructed to stop use of saline rinse approximately 
24 hours prior to the scheduled sinus CT. Daily saline irrigation should then continue following 
the sinus CT. If a subject is experiencing or recovering from a cold, acute exacerbation of nasal 
allergy, or upper respiratory tract infection at Week 25 visit, the CT assessment should be 
performed 4 weeks after resolution of the adverse event. If a subject early terminates from the 
study or requires SCS or sinonasal surgery as rescue treatment during the study, all attempts 
should be made to perform the follow-up CT before the subject receives the rescue treatment. 
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 run-in and treatment stages to avoid 
confounding the safety, pharmacokinetic, and efficacy assessments of LYR-220.  
Prohibited Concomitant Medications: 
Use of the following medications is prohibited for the duration of the study:  
x Any drug or product containing mometasone furoate (MF). 
x Oral/ocular/intramuscular/intravenous/intranasal corticosteroids (except for oral 
corticosteroids permitted as rescue medication only). 
x Antiallergy medications, including: first generation antihistamines (eg, 
diphenhydramine, dimenhydrinate, chlorpheniramine), leukotriene receptor antagonists 
(except for a stable regimen for asthma), nasal cromolyn sodium or sodium 
cromoglycate, nedocromil sodium, atropine, ipratropium bromide, or guaifenesin.  
x Oral/intranasal decongestants (except for short course of intranasal decongestants 
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x Inhaled anticholinergic medications (except for a stable regimen for subjects with 
chronic obstructive pulmonary disease [COPD]). 
x Any potent cytochrome P-450 3A4 (CYP3A4) inhibitors (eg, ketoconazole and 
ritonavir). 
x Any monoclonal antibody. 
x Any allergen immunotherapy (except for a stable dose and regimen). 
x Oral antifungal 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 instructed to use daily intranasal saline irrigation as background 
treatment starting from Screening through the study duration. 
x Subjects who have been on a stable regimen of inhaled corticosteroids (not containing 
MF) or leukotriene receptor antagonists 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 2020 Global Initiative for Asthma Management and 
Prevention.[1] 
x If acute sinus infection is suspected at any time during the study, treatment with 
antibiotics or macrolides (for a maximum of 14 days) will be allowed after a clinic visit 
and according to the Investigator’s judgment. 
x For severe acute nasal blockage lasting a minimum of 3 consecutive days: a course of 
oxymetazoline nasal decongestant sprays for a maximum of 3 consecutive days and a 
total maximum of 10 days during the treatment period. [NOTE: Oxymetazoline cannot 
be used within 24 hours before CT assessments.] 
x Nonsedating oral antihistamine such as loratadine (10 mg per day) or equivalent for 
acute allergic symptoms. 
x Perennial allergic rhinitis subjects who have been on a stable regimen of a nonsedating 
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 worsening or uncontrolled severe CRS 
symptoms that last for a minimum of 3 days and result in the subject contacting the Investigator 
who determines an initiation of rescue treatment is necessary at any time during the study:  

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x 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, or a flare-up of asthma. The dose, duration of use, and 
rationale for the use of oral corticosteroid must be recorded.  
x Sinonasal surgery as rescue treatment according to the Investigator’s recommendation. 
The type and rationale for sinonasal surgery must be recorded. 
Diagnosis and Main Criteria for Inclusion:  
Inclusion Criteria: 
A subject must meet all the following criteria to be eligible for this study: 
1. $JH years. 
2. Diagnosed as having CRS, defined by duration of 12 weeks or longer with 2 or more of 
the following symptoms: 
x nasal blockage/obstruction/congestion 
x nasal discharge (anterior, posterior, or both) 
x facial pain/pressure 
x reduction/loss of sense of smell 
3. Has had a prior bilateral ethmoidectomy involving both anterior and posterior ethmoids 
(>3 months ago). NOTE: The postsurgical ethmoid cavity should be large enough to 
accommodate the LYR-220 matrix. 
4. Has 5% opacification in the ethmoid cavity on each side on CT. 
5. SNOT-DW Screening visit.  
6. Mean 3CS score over the preceding 7 days of 4.5 (on a 0-9 scale for the total 3CS 
symptoms score) determined within 7 days of Day 1 (the determination for eligibility 
can be made on any day from Day -7 through Day 1).  
7. Not currently using INCS or decongestants at Screening or able to cease use of INCS 
and decongestants from Screening through the duration of the study. 
8. Ability to tolerate local anesthesia. 
9. 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. 
10. 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. Ethmoidectomy that was unilateral. 
2. Presence of nasal polyp grade 2 or higher, (ie, extending outside of the middle meatus) 
on either side. 
3. Endoscopic exclusion criteria at Screening and Day 1 visit:  
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b. Dense and obstructing adhesion/synechiae of ethmoid cavity that is difficult to 
separate or complete adhesion of the middle turbinate to the lateral nasal wall 
c. Severe scarring or residual ethmoid cells within ethmoid cavity preventing 
proper placement of LYR-220. 
d. Resected or degenerated middle turbinate that could interfere with retention of 
LYR-220. 
e. Evidence of mucosal erosion or ulceration within nasal cavity. 
f. Acute nasal/sinus infection or purulence.  
g. Evidence of nasal septal perforation. 
4. Screening CT exclusion criteria: 
a. Anatomic variation which, in the opinion of the Investigator, would adversely 
impact placement or retention of LYR-220. 
b. Structural, noninflammatory related CRS (eg, large concha bullosa, tumor). 
c. Sinus disease extended into orbital or intracranial space. 
d. Evidence of mycetoma/fungal ball, allergic fungal rhinosinusitis. 
e. Sinus mucocele. 
5. Seasonal allergic rhinitis (SAR) subjects with symptoms and/or, based on time of year, 
would anticipate onset of symptoms within 24 weeks of Day 1 procedure. 
6. Perennial rhinitis subjects whose symptoms are well controlled by regular use of INCS. 
7. With severe asthma or with 1 or more exacerbations of asthma requiring SCS use within 
the 3 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. 
8. History or clinical evidence or suspicion of invasive fungal sinusitis, allergic fungal 
rhinosinusitis, or atrophic rhinitis. 
9. Known history of hypersensitivity or intolerance to corticosteroids.  
10. Oral steroid or monoclonal antibody (Xolair, Nucala, Dupixent) dependent condition, 
including biologics use within 3 months of screening, per protocol clarification letter. 
11. SCS administered within 1 month prior to Screening visit. 
12. Known history of hypothalamic pituitary adrenal axial dysfunction. 
13. Previous pituitary or adrenal surgery. 
14. 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. 
15. Acute exacerbation of nasal allergy, CRS, upper respiratory tract infection (URTI), 
common cold, or clear worsening or acute change in symptoms within 4 weeks of the 
Screening visit. The infection/exacerbation must be resolved, and antibiotic or other 
medication use must be discontinued prior to screening per protocol clarification letter.  
16. Dental procedure/implant on maxillary dentition within 4 weeks of the Screening visit. 

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17. Past or present acute or chronic intracranial or orbital complications of CRS (eg, brain 
abscess, related problems with eyes or central nervous system). 
18. History or diagnosis (in either eye) of glaucoma or ocular hypertension (IOP >21 mm 
Hg). 
19. Presence (in either eye) of posterior subcapsular cataract of grade 2 or higher, nuclear 
cataract 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. 
20. Loss of functional vision in 1 or both eyes. 
21. Diagnosed with ongoing rhinitis medicamentosa. 
22. Known history of immune dysfunction including immune deficiency (IgG subclass 
deficiency or IgA deficiency) or autoimmune disease (eg, Wegener’s granulomatosis, 
sarcoidosis) that requires immunomodulatory therapy. NOTE: Autoimmune conditions 
that do not require immunomodulatory therapy are not exclusionary.  
23. Past, present, or planned organ transplant or chemotherapy with immunosuppression. 
24. History or diagnosis of ciliary dysfunction (eg, cystic fibrosis, primary ciliary 
dyskinesia [Kartagener syndrome]).  
25. Past or present systemic vasculitis (eg, granulomatosis with polyangiitis). 
26. Evidence of disease or condition expected to compromise survival or ability to complete 
follow-up assessments. 
27. 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 on 
Day 1 prior to the time of treatment 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. 
28. Previously received an experimental treatment in another clinical study within 5 half-
lives or 30 days (whichever is longer) of Screening visit.  
29. Currently participating in another drug or device study.  
30. Currently positive for COVID-19 or residual sinonasal symptoms from a previous 
COVID-19 infection. 
31. 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-220 System is a combination product comprised of a single-use applicator, preloaded 
with an anti-inflammatory LYR-220 drug matrix [referred to as LYR-220 in this document]. 
LYR-220 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 CRS disease, as well as asthma. LYR-220 is designed to gradually soften over 

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time and is made of bioabsorbable polymers that have been used as components of approved 
pharmaceutical drugs and/or medical devices. 
Each LYR-220 contains a total MF dose of 7500 μg. LYR-220 is intended to be administered 
bilaterally into the ethmoid cavity, in which ethmoid sinuses have been removed previously by 
ethmoidectomy, by an otolaryngologist under endoscopic visualization using the provided 
single-use applicator. Once administered, each LYR-220 is designed to gradually deliver 
sustained doses of MF to the inflamed mucosal tissue over a 24-week resident time. Bilateral 
placement of LYR-220 is designed to deliver a total dose of 15,000 μg MF over the 24 weeks, 
or an average daily dose of 89 μg MF per person (or 45 μg MF per nostril).   
The LYR-220 drug matrix has a tubular braid configuration with a uniform diamond pattern 
throughout. It is designed to be self-retaining against the mucosal tissue to allow effective drug 
transfer for up to 24 weeks. The matrix is comprised of a base structure and a drug formulation 
layer. The base structure is composed of poly(L-lactide-co-glycolide) and poly(L-lactide-co-İ-
caprolactone) elastomer to provide a 3-dimensional structure and elasticity. The drug 
formulation layer consists of the active ingredient, MF, embedded in the inactive ingredients 
containing poly(L-lactide-co-İ-caprolactone) and poly(L-lactide) to control the release rate of 
MF. Two designs of LYR-220, LYR-220-32 drug matrix and LYR-220-16 drug matrix, 
manufactured with 32 and 16 woven fibers, respectively, will be assessed in Part 1 of this 
study. Both designs have the same nominal dimensions of 20 mm in diameter and 16 mm in 
length in the unconstrained state. 
For the sham treatment, a single-use LYR-220 sham applicator is introduced to the sinus cavity. 
The sham applicator does not contain a preloaded LYR-220 drug matrix. 
Duration of Study:  
The total duration of the study, including the enrollment period, is approximately 14 months. 
Each enrolled subject is planned to participate in the study for a total duration of approximately 
8 months, which includes the Screening/Run-in, Treatment, and Posttreatment 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: 
Sample Size: 
Because the primary objective of this study is to evaluate the safety, tolerability, and 
pharmacokinetics of LYR-220, the sample size determination is not based on statistical power 
considerations. Up to 10 subjects will be treated during the part 1 phase and approximately 20 
subjects per treatment arm will be enrolled during the part 2 randomized phase (40 total). 
 
Analysis Sets: 

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x Safety analysis set: All subjects who received the study treatment. Subjects will be 
analyzed according to the treatment received. This is the primary analysis set for 
assessment of safety. 
x Efficacy analysis set: All subjects who received the study treatment. This is the primary 
analysis set for assessment of efficacy. Subjects will be analyzed according to the 
treatment they actually received. 
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 (SD), 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: 
Subject disposition will be summarized for all consented subjects. Analysis set assignment will 
be summarized for all enrolled subjects by treatment group. Demographics and other baseline 
characteristics and study drug exposure will be summarized for the Efficacy analysis set.  
PK Analyses: 
The PK analyses will be performed based on subjects with available plasma MF concentration 
data post Day 1 LYR-220 administration procedure. A summary table will be used to present 
descriptive statistics (number, mean, SD, coefficient of variation, median, minimum, and 
maximum) of these PK parameters by treatment group. If plasma MF levels are detectable, PK 
parameters of MF will be estimated using a standard noncompartmental PK approach based on 
individual plasma concentration-time data. Maximum concentration (Cmax) and time to reach 
maximum concentration (Tmax) will be taken directly from the observed data. Actual PK 
sampling times will be used in the derivation of PK parameters. There will be no imputation of 
missing data. 
Safety Analyses: 
Safety will be assessed through AEs and changes in laboratory tests, vital signs, nasal 
endoscopy assessment, IOP and slit-lamp examination using the safety analysis 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. There will be no 
imputation of missing data.  
 
Efficacy Analyses: 

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All efficacy analyses will be carried out after the last subject completes the Week 28 visit or 
withdraws prematurely prior to Week 28.  
A mixed model repeated measures (MMRM) approach will be used to compare changes from 
baseline (CFBL) between LYR-220 group and the sham procedure group in SNOT-22, CRS-
PRO, PGIS, and CS scores. An analysis of covariance (ANCOVA) model will be used to 
analyze the CT score and biomarker levels. 
Efficacy data collected after early termination will be included in the analysis. A last 
observation carried forward (LOCF) method will be used to impute post rescue treatment and 
missing data. Rescue treatment include SCS and/or sinonasal surgery for any reason. There will 
be no imputation for missing follow-up CT or biomarker assessments. 
 

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2. 
INTRODUCTION 
2.1 
Chronic Rhinosinusitis  
Chronic rhinosinusitis (CRS) is a common condition that is defined by symptomatic 
inflammation of the paranasal sinuses lasting longer than 12 weeks. CRS affects approximately 
4.9% of the US population, which is about 14 million people[2], and 10.9% of the European 
population.[3] In the US, approximately 8 million people are treated for CRS by physicians each 
year,[4] of which approximately 4 million fail medical management.[5] Moreover, CRS results in 
18 million annual office visits[6] and direct treatment costs of more than $60 billion annually in 
the US,[7] including approximately $5 billion on sinus surgeries.  
CRS has 2 main phenotypes, CRS with nasal polyps (CRSwNP) and CRS without nasal polyps 
(CRSsNP), with CRSsNP representing 70-90% of patients. The cardinal symptoms of CRS 
include nasal blockage/obstruction/congestion, facial pressure/pain, nasal discharge 
(anterior/posterior nasal drip), and reduction or loss of smell.[8, 9] The underlying cause of CRS-
related symptoms is inflammation of mucosal tissues leading to impairment of mucociliary 
clearance.  
Medical and surgical interventions are directed toward managing the symptoms of CRS. 
Currently, there are no FDA-approved drug therapies for CRSsNP, although 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 corticosteroids with 
adjunctive use of daily nasal saline irrigation.[10] However, inefficient drug delivery to the 
inflamed mucosal tissues[11] and poor patient compliance limit the effectiveness of such 
therapy.[12] Flare-ups and worsening inflammation or severe nasal polyps are typically managed 
with a short course (1-3 weeks) of oral corticosteroids.[8, 9] While effective initially, 
improvements are typically not sustained for longer than 3 months.[13, 14] Additionally, oral 
corticosteroids can lead to systemic side effects including mood disturbance, gastrointestinal 
issues, diabetes, cataracts, glaucoma, and osteoporosis,[15, 16] which have limited their routine 
use. Approximately 50% of patients fail medical management[17] and become potential 
candidates for functional endoscopic sinus surgery (FESS). FESS removes inflamed tissues and 
bone to open the sinonasal passages to facilitate normal sinus drainage and aeration and provide 
greater access for delivery of topical steroids. Approximately 400,000 FESS procedures are 
performed each year,[17] and Lyra estimates approximately 40% of patients that present to an 
otolaryngologist with CRS have had a prior FESS. Given the essential role of the ethmoid bulla 
in sinus function, the ethmoid sinuses are opened in approximately 80% of FESS procedures.[18] 
Of the ethmoidectomies performed by an otolaryngologist, Lyra estimates approximately one-
third are anterior or partial, and two-thirds are total. Although FESS can improve symptoms and 
quality of life, it does not correct the underlying cause of the inflammation nor obviate the need 
for continued medical management, primarily consisting of intranasal corticosteroids and nasal 
saline. Furthermore, approximately, 65% of patients have recurrent symptoms post FESS within 
the first year[19] and up to 20% elect a revision surgery.[20]  

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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 perennial allergic 
rhinitis (AR), nasal polyps, a phenotype of CRS disease, (Nasonex®[21]), as well as asthma 
(Asmanex® Twisthaler®[22]). Propel®[23] and Sinuva™[24] are FDA-approved MF-eluting sinus 
implants placed in adults following ethmoid sinus surgery to maintain patency, and in the 
ethmoid sinus for up to 90 days for the treatment of recurrent nasal polyps in adults who have 
had ethmoid sinus surgery, respectively. CRS is characterized by inflammation of the mucosal 
membrane of the sinonasal cavities. Corticosteroids have a long history of use and have been 
shown to have a wide range of effects on multiple cell types (eg, mast cells, eosinophils, 
neutrophils, macrophages, and lymphocytes) and mediators (eg, histamine, eicosanoids, 
leukotrienes, and cytokines) involved in inflammation. Results from pharmacokinetics (PK) 
studies in adults and children suggest that systemic exposure to MF after intranasal 
administration is negligible, underscoring MF as an ideal drug candidate for the development of 
an optimal topical drug formulation for CRS patients with and without polyps who have had a 
prior ethmoidectomy.  
Drug-eluting implantable treatments have demonstrated the ability to provide therapy directly to 
the local site of disease in a sustained fashion while eliminating systemic effects of the drug.[25, 
26] Propel®  and Sinuva™ are topical MF-eluting nasal implants recently developed for patients 
immediately following ethmoid sinus surgery or for patients with recurrent polyposis post-
ethmoid sinus surgery, that demonstrated clinical benefits over a no-drug implant control[27, 28] or 
a sham-procedure control[29, 30], respectively. The American Rhinologic Society (ARS) endorsed 
the utilization of steroid-eluting drug delivery implants into the paranasal sinuses for their 
demonstrated improvement of patient outcomes and limiting the need for oral steroids.[31] 
Recently, the FDA approved 2 monoclonal antibody therapies targeting aspects of Type 2 
inflammation in CRSwNP patients: dupilumab[32] and omalizumab[33]. Despite their efficacy, 
these drugs are systemic in nature, their long-term safety profile is unknown, and they have 
annual costs exceeding $30,000 per patient in the US. 
An ideal treatment for CRS patients with and without nasal polyps that have undergone an 
ethmoidectomy and have recurrent symptoms would provide local, sustained, anti-inflammatory 
drug delivery directly to the inflamed sinonasal mucosal tissues over a longer period of time and 
at a higher dose than what is currently available in a single administration. Such a therapy would 
be safe and tolerable throughout the entire treatment duration and not depend upon patient 
compliance. It would conform to the patient’s operated ethmoid cavity and maintain prolonged 
mucosal contact with local drug absorption and minimal depletion. It would also allow for 
straightforward in-office placement and removal and resorb safely in case any remnants are left 
behind.  
The LYR-220 drug matrix is comprised of 7500 μg of MF, embedded in a bioabsorbable 
polymer matrix allowing for controlled, sustained, and targeted release of MF for 24 weeks in a 

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single administration. The LYR-220 drug matrix is designed to fit within the ethmoid cavity in 
patients who have had a prior ethmoidectomy and maintain contact with the mucosa throughout 
the 24-week duration of drug delivery. LYR-220 is intended to be administered bilaterally into 
the previously operated ethmoid cavities by an otolaryngologist under endoscopic visualization 
using the provided single-use applicator. The administration of LYR-220 is office-based and 
performed with local anesthesia. LYR-220 can be removed at 24 weeks or earlier at the 
physician’s discretion using standard instruments. LYR-220, if approved, is positioned for use in 
patients who despite previous sinus surgery continue to have recurrent CRS symptoms as a 
potential preferred alternative to revision surgery. LYR-220 is meaningfully differentiated from 
currently approved products for CRS patients that have undergone a FESS, because it would be 
the only product able to deliver up to six months of topical treatment in a single administration. 
Furthermore, unlike the monoclonal antibody therapies, LYR-220 would provide localized 
delivery which avoid systemic side effects. 
The safety and efficacy of MF at the dose level of 2500 and 7500 μg MF delivered over 24 
weeks in CRS patients have been evaluated previously by Lyra Therapeutics in Phase I 
(ClinicalTrials.gov ID: NCT02967731) and Phase II (ClinicalTrials.gov ID: NCT04041609) 
clinical studies in adult CRS patients who have failed previous medical management and have 
not undergone endoscopic sinus surgery. The LYR-210 clinical results indicated that LYR-210 is 
safe and well-tolerated in CRS patients with undisrupted middle meatuses. The LYR-210 (7500 
μg) dose in the dose-ranging Phase 2 study clearly demonstrated clinically meaningful sinonasal 
symptoms improvement compared to a control group. Safety and efficacy summary of LYR-210 
in humans can be found in the IB and in published literature[34]. These clinical experiences with 
LYR-210 in surgically naïve CRS subjects suggest encouraging clinical benefits of the 7500 μg 
MF-eluting drug matrix over the 24-week of drug delivery, while avoiding safety risks associated 
with prolonged oral steroid treatment. 
2.3 
Study Rationale 
Lyra Therapeutics is conducting a multicenter study in a patient-blinded, two-part, randomized, 
parallel group manner in approximately 50 symptomatic adult CRS subjects who have had a 
prior bilateral ethmoidectomy. The study will consist of two parts. The safety, tolerability, 
pharmacokinetics, and efficacy of two designs, the LYR-220-32 (7500 μg) drug matrix and the 
LYR-220-16 (7500 μg) drug matrix, will be assessed through 28 weeks in Part 1 of the study.  In 
addition to the safety and pharmacokinetics assessments of LYR-220, in part 1 of the study, the 
primary objective is to evaluate the feasibility of placement and optimize the LYR-220 insertion 
procedure before beginning part 2 of the study. [Note: Subject enrollment in part 2 can begin 
after subjects in part 1 have undergone the LYR-220 insertion procedure; subjects in part 1 do 
not need to complete a certain amount of follow-up prior to part 2 commencing.] The efficacy of 
the LYR-220-32 (7500 μg) drug matrix will also be evaluated through 28 weeks by comparing to 
a sham treatment control. A sham treatment control is included to reduce bias in subject reported 
efficacy outcomes. Subjects enrolled in part 2 will be blinded to the treatment assignment 
throughout the 28-week study duration.  
 

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3. 
STUDY OBJECTIVES AND ENDPOINTS 
The study objectives and endpoints are:  
Study Objectives 
Study Endpoints 
Primary  
To evaluate unexpected serious 
adverse events related to LYR-220 
- Product-related unexpected serious adverse events 
Pharmacokinetics 
To evaluate the pharmacokinetics 
of LYR-220 
- Plasma MF concentrations at 1 hour (±10 minutes) post 
study treatment administration and at Days 2 or 3, and 
Days 5 or 8, and Weeks 4, 12, 16 or 20, 24, and 25  
Secondary - Safety 
To evaluate the safety and 
tolerability of LYR-220 
- Treatment-emergent adverse events (TEAEs) and 
serious adverse events (TESAEs) through Week 28 
- Clinically significant abnormal laboratory values 
(hematology and chemistry) through Week 25 
- Newly identified or worsened endoscopic findings 
(epistaxis and mucosal injury) in ethmoid cavity through 
Week 25 
- Clinically significant increase of IOP through Week 25 
A clinically significant increase of IOP is defined as 
IOP in 1 or both eyes >23 mm Hg or an increase of IOP 
from Baseline in one or both eyes 10 mm Hg. 
- Newly identified or worsened cataract in 1 or both eyes 
by slit-lamp examination through Week 25 
Secondary - Efficacy 
To evaluate the efficacy of LYR-
220 in improving total SNOT-22 
and subdomain scores through 
Week 28  
- Change from baseline (CFBL) in SNOT-22 total and 
subdomain scores at Weeks 2, 4, 6, 8, 12, 16, 20, 24, 
and 28 
The SNOT-22 questionnaire is a 22-item disease-
specific quality of life instrument validated for use in 
CRS. Each symptom is scored as it has been over the 
past 2 weeks on a 6-point scale as follows: 0 = no 
problem, 1 = very mild problem, 2 = mild or slight 

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problem, 3 = moderate problem, 4 = severe problem, 5 
= problem as bad as it can be. 
To evaluate the efficacy of LYR-
220 in improving 3CS and 
individual cardinal symptom score 
through Week 28 
- CFBL in the average composite score over the 
preceding 7 days of 3 cardinal symptoms (3CS) and 
individual cardinal symptom scores at Weeks 2, 4, 6, 8, 
12, 16, 20, 24, and 28 
The 3 cardinal symptoms include nasal 
blockage/obstruction/congestion, facial pain/ pressure, 
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. 
To evaluate the efficacy of LYR-
220 in improving loss of smell 
symptom score through Week 28 
for subjects with moderate-to-
severe score at baseline 
- CFBL in average loss of smell score over the preceding 
7 days for all subjects and subjects with baseline score 
DWWeeks 2, 4, 6, 8, 12, 16, 20, 24, and 28 
To evaluate the efficacy of LYR-
220 in improving total Patient-
Reported Outcome Measure for 
Chronic Rhinosinusitis (CRS-
PRO) and subdomain scores 
through Week 28 
- Change from baseline (CFBL) in Patient-Reported 
Outcome Measure for Chronic Rhinosinusitis (CRS-
PRO) total and subdomain scores at Day 8 and Weeks 
2, 3, 4, 6, 8, 12, 16, 20, 24, and 28 
The CRS-PRO questionnaire is a 12-item disease-
specific health-related impairment for use in CRS. Each 
symptom is scored as it has been over the past 7 days on 
a 5-point scale as follows: 0 = not at all, 1 = a little bit, 
2 = somewhat, 3 = quite a bit, 4 = very much. 
To evaluate the time to first rescue 
treatment recommendation 
through Week 28 
- Time to first rescue treatment recommendation through 
Week 28 
Rescue treatment is defined as, after subject enrollment, 
worsening or acute exacerbation of CRS in a subject 
resulting in the treating physician reporting an 
escalation of treatment, including systemic 
corticosteroids (SCS), and/or sinonasal surgery. Rescue 
treatment is not recommended if worsening of symptoms 
is for less than 3 days duration.  
To evaluate the percentage of 
subjects who have uncontrolled 
CRS symptoms requiring oral 
- Oral steroid use or sinonasal surgery recommendation 
through Week 28 

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steroids or sinonasal surgery 
through Week 28 
To evaluate the effect of LYR-220 
in reducing ethmoid cavity 
opacification as per CT 
- CFBL in bilateral percent ethmoid cavity opacification 
by CT at Week 25 
To evaluate the efficacy of LYR-
220 in improving subject 
perception of symptom severity 
and improvement 
- CFBL in the Patient Global Impression of Severity 
(PGIS) score at Weeks 8, 16, and 24 
- Patient Global Impression of Change (PGIC) score at 
Week 24 
To evaluate the effect of LYR-220 
in converting a subject to not 
requiring revision surgery 
- No longer a candidate for revision surgery 
Subjects will be deemed as having converted if they do 
not undergo revision sinonasal surgery (planned or 
actual) during the study and if they meet the following 
criteria: 
x 3CS score 4 at Week 24, or 
x No disease in ethmoid cavities on Week 25 CT  
To evaluate the effect of LYR-220 
in reducing nasal inflammatory 
marker levels at Week 25 
- CFBL in nasal inflammatory marker levels at Week 25 
 
 
 

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4. 
INVESTIGATIONAL PLAN 
4.1 
Overall Study Design 
This multicenter study will be conducted in an open-label, two-part, randomized, parallel-group 
manner in approximately 50 symptomatic adult subjects with CRS who have had a prior bilateral 
ethmoidectomy. The safety, tolerability, pharmacokinetics, and efficacy of 2 designs, LYR-220-
32 drug matrix and LYR-220-16 drug matrix, will be assessed in Part 1. Both designs of LYR-
220 matrices contain 7500 μg of mometasone furoate (MF). 
The study will consist of 2 parts. In part 1 of the study, up to 10 subjects will be treated with 
either design of LYR-220 bilaterally. The primary objective of the part 1 study, in addition to the 
safety and pharmacokinetics assessments of LYR-220, is to evaluate the feasibility of placement 
and optimize the LYR-220 insertion procedure, if necessary, before beginning part 2 of the 
study, in which approximately 40 subjects (20 per treatment arm) will be randomized 1:1 to 
either LYR-220-32 (7500 ug) or a sham procedure.  
Each subject will undergo 3 stages during the study:  
x Screening and Run-in Stage: 2-4 weeks  
x Treatment Stage: 24 weeks  
x Post-treatment Follow-Up Stage: 4 weeks 
The overall study design 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 and Run-in 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 2–4-week run-in period. The run-in period is more than 5 elimination half-lives of 
MF (5.8 hours)[35] as recommended by FDA guidelines.[36] During this run-in period, except for a 
background therapy of daily saline irrigation, subjects will receive no other active treatment for 
CRS or any prohibited or rescue medications specified in the study protocol (Sections 6.4.2 and 
6.4.4, respectively).  
If a subject fails the initial screening, they are permitted to be rescreened under a new subject ID. 
If a patient is eligible for rescreening, the sinus CT and IOP/slit lamp assessments do not need to 
be repeated if the assessments were done within 4 months of rescreening and there were no 
significant changes in the subject’s medical history according to the Investigator’s judgement. 
Subjects who fail screening due to administrative reasons (eg, visit window) or another screening 
assessment may be allowed to repeat certain screening assessment(s) and re-establish eligibility. 
Documentation of the decision will be filed in the subject’s file.  
Subjects will be provided with saline and instructions for daily intranasal saline irrigation 
starting from the Screening visit throughout the study. Subjects will be instructed to stop use of 
saline rinse approximately 24 hours prior to the scheduled sinus CT. Daily saline irrigation 
should then continue following the sinus CT. Daily saline irrigation procedures should adhere to 
the Investigator’s prescribing information and local standards, as applicable. 
Beginning at least 14 days prior to LYR-220 insertion procedure on Treatment Day (Day 1), 
subjects will record daily cardinal symptoms (CS) of CRS on the electronic patient-reported 
outcomes (ePRO) questionnaire. At Screening, the SNOT-22 and CRS-PRO will also be 
collected. 
4.1.2 
Treatment Stage 
The total duration of the Treatment Stage will be approximately 24 weeks.  
In the part 1 of the study, on Day 1, subjects will be treated with any design of LYR-220 
bilaterally. The LYR-220 insertion procedure will be assessed and optimized, if necessary, 
before the randomized part 2 phase. [Note: Subject enrollment in part 2 can begin after subjects 
in part 1 have undergone the LYR-220 insertion procedure; subjects in part 1 do not need to 
complete a certain amount of follow-up prior to part 2 commencing.] In the part 2 of the study, 
on Day 1, before any treatment, subjects will be randomized in a 1:1 ratio to 1 of the 2 study 
arms:  
x Treatment Arm A: bilateral insertion of LYR-220-32 (7500 μg)  
x Treatment Arm B: bilateral sham procedure 
Subjects in part 2 of the study will be stratified for treatment assignment according to the 
following criteria: 
x Nasal polyps (Yes vs No) 

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No more than 10 subjects with polyps will be enrolled in each treatment arm. 
On Day 1, after completing any required pretreatment baseline assessments, subjects will receive 
local anesthetic and may receive decongestants in the ethmoid cavity for endoscopic assessment 
and in preparation for the insertion procedure.  
All subjects will return to clinic for the scheduled follow-up assessments at Day 2 or 3, Day 5 or 
8, Week 4, Week 12, Week 16 or 20, and Week 24 visits. Subjects will receive telephone follow-
ups at Week 8 and Week 16 or 20 (ie, the week they are not scheduled to attend in-clinic visit for 
PK blood draw) 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 have received LYR-220 will have the bilateral matrices removed 
using standard surgical tools. Subjects in the sham treatment control arm will have a sham 
removal procedure. 
If spontaneous dislodgement of LYR-220 occurs before the scheduled Week 24/EOT visit, 
subjects are required to call the study clinic immediately to report the event. If a subject 
experiences dislodgement of 1 of the bilateral matrices, the subject will continue in the treatment 
phase unless an early treatment discontinuation is recommended by the treating physician or 
subject requests matrix removal from the remaining side of the nose. If matrices spontaneously 
dislodge from both sides of the nose, the subject will complete an unscheduled early-
termination (ET) visit within 7 days of the second matrix dislodgement, and complete the 
assessments scheduled for the Week 24/EOT visit. Spontaneously dislodged LYR-220 should be 
retained, if available, and returned to the clinic at subject’s next visit. 
If medically warranted according to the treating physician’s discretion (for example, needing 
sinonasal surgery as rescue treatment), early matrix removal may be performed at an 
unscheduled ET visit.  
Any subject who undergoes an ET visit is required to complete the assessments scheduled for the 
Week 24/EOT visit and should stay in the study and complete the assessments scheduled for the 
Week 25 visit within 5-9 days after the ET visit.  
4.1.3 
Post-treatment Follow-Up Stage 
All subjects will undergo a 1-week post-treatment follow-up visit (Week 25 visit). AEs, 
concomitant medications/procedures, endoscopy, nasal swabs, ophthalmologic assessments, CT, 
and other scheduled assessments will be performed at Week 25 visit. In addition, subjects will 
complete a 4-week post-treatment follow-up by telephone or in-clinic visit [Week 28/end-of-
study (EOS)]. End of study assessments include AEs, concomitant medications/procedures, and 
final ePROs (4CS, SNOT-22, CRS-PRO, and End-of-Study Questionnaire). 
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. 

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4.2 
Rationale for Study Design 
The primary objective of this study is to evaluate the safety, tolerability, and pharmacokinetics in 
subjects receiving LYR-220. The study design and endpoints are adequate for assessments of 
safety and pharmacokinetics of LYR-220 in adult subjects with CRS. The assessments of 
systemic and local nasal parameters in this study’s CRS population and in the context of in situ 
drug delivery via drug matrix are appropriate for safety signal detection. The assessments of 
plasma MF concentration are sufficient to evaluate drug release profile of LYR-220. The 
secondary objective of this study is to determine the efficacy of LYR-220 in improving CRS 
symptoms. A sham treatment arm is added as a control for evaluating the LYR-220 treatment 
responses against control. The SNOT-22 and CRS-PRO questionnaires have been selected 
because they are disease specific to analyze quality of life. The 4CS questionnaire is used to 
evaluate daily cardinal symptoms of CRS subjects. Computed tomography (CT) scan is the gold 
standard diagnostic radiological tool for CRS and is adequate to evaluate the opacification of 
ethmoid cavity in the study subject population. The measurement of changes in nasal 
inflammatory marker levels is appropriate for development and further refinement of study 
objective endpoints in the clinical program. The safety rationale for the selection of drug dose 
and polymers in LYR-220 are summarized in the Investigator’s Brochure (IB).  
4.3 
Discontinuation of Study Subjects 
Subjects will be encouraged to complete the study through the post-treatment follow-up period. 
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 for any of the 
following reasons: 
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-220 (Section 6.5).
x
Any serious AE (SAE, Section 8.3.11.2), 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 sinonasal surgery as rescue treatment.
x
If deviations to the use of prohibited medications occur during run-in and study
treatment periods, 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.

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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 and EOS visits (Section 
8.1).  
The Investigator or study staff will document the reason(s) for subject discontinuation on the 
electronic Case Report Form (eCRF), notify the EC/IRB as required by their Institution’s 
procedures, and notify the Sponsor of the reason for discontinuation. 
4.4 
Criteria for Study Termination 
If the Sponsor, the Investigator, the medical monitor, EC/IRB, 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 EC/IRB, and the medical monitor. Refer to Section 
10.13 for additional information. 
 
 

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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 EC/IRB-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. Subject 
identification 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 (eCRFs).  
Subjects who fail screening due to administrative reasons (eg, visit window) or another screening 
assessment may be allowed to repeat certain screening assessment(s) and re-establish eligibility. 
Documentation of the decision will be filed in the subject’s file.  
5.2 
Subject Informed Consent 
Prior to enrollment in the study, all subjects must review and complete an EC/IRB-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. $JH years. 
2. Diagnosed as having CRS, defined by duration of 12 weeks or longer with 2 or more of 
the following symptoms: 
x nasal blockage/obstruction/congestion 
x nasal discharge (anterior, posterior, or both) 
x facial pain/pressure 
x reduction/loss of sense of smell 
3. Has had a prior bilateral ethmoidectomy involving both anterior and posterior ethmoids 
(>3 months ago). NOTE: The postsurgical ethmoid cavity should be large enough to 
accommodate the LYR-220 matrix. 
4. Has RSDFLILFDWLRQin the ethmoid cavity on each side on CT. 
5. SNOT-DW Screening visit.  

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6. Mean &6VFRUHRYHUWKHSUHFHGLQJGD\VRI(on a 0-9 scale for the total 3CS 
symptoms score) determined within 7 days of Day 1 (the determination for eligibility can 
be made on any day from Day -7 through Day 1).  
7. Not currently using INCS or decongestants at Screening or able to cease use of INCS and 
decongestants from Screening through the duration of the study. 
8. Ability to tolerate local anesthesia. 
9. 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. 
10. 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. Ethmoidectomy that was unilateral. 
2. Presence of nasal polyp grade 2 or higher (ie, polyps extending outside of the middle 
meatus) on either side. 
3. Endoscopic exclusion criteria at Screening and Day 1 visit:  
a. Obstructing the nasal cavity for proper placement or retention of LYR-220. 
b. Dense and obstructing adhesion/synechiae of ethmoid cavity that is difficult to 
separate or complete adhesion of the middle turbinate to the lateral nasal wall. 
c. Severe scarring or residual ethmoid cells within ethmoid cavity preventing proper 
placement of LYR-220. 
d. Resected or degenerated middle turbinate that could interfere with retention of 
LYR-220.  
e. Evidence of mucosal erosion or ulceration within nasal cavity. 
f. Acute nasal/sinus infection or purulence. 
g. Evidence of nasal septal perforation. 
4. Screening CT exclusion criteria: 
a. Anatomic variation which, in the opinion of the Investigator, would adversely 
impact placement or retention of LYR-220. 
b. Structural, noninflammatory related CRS (eg, large concha bullosa, tumor). 
c. Sinus disease extended into orbital or intracranial space. 
d. Evidence of mycetoma/fungal ball, allergic fungal rhinosinusitis. 
e. Sinus mucocele. 
5. Seasonal allergic rhinitis (SAR) subjects with symptoms and/or, based on time of year, 
would anticipate onset of symptoms within 24 weeks of Day 1 procedure. 
6. Perennial rhinitis subjects whose symptoms are well controlled by regular use of INCS. 
7. With severe asthma or with 1 or more exacerbations of asthma requiring SCS use within 
the 3 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. 

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8. History or clinical evidence or suspicion of invasive fungal sinusitis, allergic fungal 
rhinosinusitis, or atrophic rhinitis. 
9. Known history of hypersensitivity or intolerance to corticosteroids.  
10. Oral steroid or monoclonal antibody (Xolair, Nucala, Dupixent) dependent condition, 
including biologics use within 3 months of screening per protocol clarification letter. 
11. SCS within 1 month prior to Screening visit. 
12. Known history of hypothalamic pituitary adrenal axial dysfunction. 
13. Previous pituitary or adrenal surgery. 
14. 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. 
15. Acute exacerbation of nasal allergy, CRS, upper respiratory tract infection (URTI), 
common cold, or clear worsening or acute change in symptoms within 4 weeks of the 
Screening visit. The infection/exacerbation must be resolved, and antibiotic or other 
medication use must be discontinued prior to screening per protocol clarification letter. 
16. Dental procedure/implant on maxillary dentition within 4 weeks of the Screening visit. 
17. Past or present acute or chronic intracranial or orbital complications of CRS (eg, brain 
abscess, related problems with eyes or central nervous system). 
18. History or diagnosis (in either eye) of glaucoma or ocular hypertension (IOP >21 mm 
Hg). 
19. Presence (in either eye) of posterior subcapsular cataract of grade 2 or higher, nuclear 
cataract 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. 
20. Loss of functional vision in 1 or both eyes. 
21. Diagnosed with ongoing rhinitis medicamentosa. 
22. Known history of immune dysfunction including immune deficiency (IgG subclass 
deficiency or IgA deficiency) or autoimmune disease (eg, Wegener’s granulomatosis, 
sarcoidosis) that requires immunomodulatory therapy. NOTE: Autoimmune conditions 
that do not require immunomodulatory therapy are not exclusionary. 
23. Past, present, or planned organ transplant or chemotherapy with immunosuppression. 
24. History or diagnosis of ciliary dysfunction (eg, cystic fibrosis, primary ciliary dyskinesia 
[Kartagener syndrome]).  
25. Past or present systemic vasculitis (eg, granulomatosis with polyangiitis). 
26. Evidence of disease or condition expected to compromise survival or ability to complete 
follow-up assessments. 
27. 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 on 
Day 1 prior to the time of treatment 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. 

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28. Previously received an experimental treatment in another clinical study within 5 half-
lives or 30 days (whichever is longer) of Screening visit.  
29. Currently participating in another drug or device study.  
30. Currently positive for COVID-19 or residual sinonasal symptoms from a previous 
COVID-19 infection. 
31. 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 
Subject Allocation 
6.1.1 
Enrollment 
Approximately 50 subjects who complete the study Screening assessments and the run-in period 
and meet all eligibility criteria will be enrolled and treated bilaterally with either the LYR-220-
32 design or a sham treatment on Day 1 (as described in Section 4.1). 
For any reason, if the Investigator is unable to successfully administer LYR-220 into both 
ethmoid cavities in a subject (as described in Section 6.2.4), this subject will be considered as an 
Enrollment Failure. 
6.1.2 
Randomization (Part 2 Study Only) 
Approximately 40 subjects who complete the study Screening assessments and the run-in period, 
and meet all eligibility criteria on Day 1 in the part 2 of the study will, before any treatment, be 
randomized in a 1:1 ratio to 1 of the 2 study arms: 
x Treatment Arm A: bilateral insertion of LYR-220-32 (7500 μg)  
x Treatment Arm B: bilateral sham treatment control 
Subjects will be stratified for treatment assignment according to the following criteria: 
x Nasal polyps (Yes vs No) 
No more than 10 subjects with nasal polyps will be assigned to each treatment arm. Treatment 
will be assigned according to a randomization scheme generated by the Sponsor or designee. 
Randomization will be conducted using Interactive Response Technology (IRT). 
6.2 
Study Product Administration 
6.2.1 
Pre-procedure Medication 
Prior to LYR-220 administration, all subjects will receive local anesthetic and decongestants in 
the ethmoid cavity for endoscopic assessment and in preparation for the insertion procedure 
according to the individual clinic/site standards. 
6.2.2 
Study Product Preparation 
LYR-220 and sham products will be provided to the study site as described in Section 7.2.1. 
Preparation of LYR-220 and the sham product should be performed in accordance with the 
instructions for use (IFU) provided in a separate document and should not start until the subject 
has been prepared, anesthetized, and is ready for the insertion procedure.  
6.2.3 
Study Product Administration 
LYR-220 is designed to be administered intranasally under endoscopic visualization. Subjects 
who are assigned to either design of LYR-220 will have LYR-220 administered bilaterally into 
the ethmoid cavity. Subjects who are assigned to the sham procedure arm, will undergo bilateral 
mock administration (ie, sham procedure), consisting of a bilateral insertion of an applicator 
(without LYR-220 matrix) into the ethmoid cavity until the applicator tip touches the posterior 

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wall of the ethmoid cavity for a minimum of 20 seconds, followed by withdrawal of the 
applicator. To maintain subject blinding to the treatment assignment in part 2 of the study, 
subjects will wear an eye mask (ie, blindfold) and ear/headphones at the time of the LYR-220 
administration/sham procedure. A Sponsor representative/case manager may be present during 
Day 1 visit to provide guidance regarding product administration. 
Following administration procedure, all enrolled subjects should be monitored to ensure there is 
no epistaxis or any other untoward conditions that requires medical attention. Subjects should 
remain in/around the clinic and complete any further assessments (such as the 1-hour post 
procedure PK blood draw) until they are cleared to leave by the study clinic personnel. 
6.2.4 
Enrollment Failure 
The Investigator will be allowed up to 2 attempts at LYR-220 administration per side. If the 
Investigator is unable to administer LYR-220 bilaterally into both ethmoid cavities of a subject, 
the Investigator will remove any LYR-220 already administered and treat the subject with any 
appropriate therapy, if necessary. The subject will be considered as an Enrollment Failure. 
Follow-up with subjects will occur within 7 (± 2) days by telephone for AE and concomitant 
medication assessments. 
6.2.5 
End of Day 1 Visit 
Prior to discharge at Day 1 visit, the study staff will remind enrolled subjects of the following:  
x That they are currently enrolled in an investigational study for up to 6 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 an open mouth 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-220 falls out of the nose.  
6.3 
Blinding 
Subjects should remain blinded to their treatment assignment until the final study database is 
locked. To maintain subject blinding (LYR-220 or sham) in part 2 of the study, each subject will 
wear an eye mask (ie, blindfold) and ear/headphones at the time of the LYR-220 
administration/sham procedure and at all post Day 1 visits (scheduled or unscheduled) during 
any endoscopy assessments and during the LYR-220 administration/sham removal procedure. 
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-220, 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. 

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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 run-in and treatment stages to avoid 
confounding the safety, pharmacokinetic, and efficacy assessments of LYR-220.  
6.4.1 
Prior Medications 
Beginning at Screening, all medications and other treatments taken by subjects will be recorded 
on the concomitant medications 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 
(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 
may contact the Sponsor’s medical monitor for guidance prior to administration as needed, 
provided the safety of the subject would not be compromised. 
6.4.2 
Prohibited Concomitant Medications 
Use of the following medications is prohibited for the duration of the study:  
x Any drug or product containing mometasone furoate (MF). 
x Oral/ocular/intramuscular/intravenous/intranasal corticosteroids (except for oral 
corticosteroids permitted as rescue medication only). 
x Anti-allergy medications, including: first generation antihistamines (eg, 
diphenhydramine, dimenhydrinate, chlorpheniramine), leukotriene receptor antagonists 
(except for a stable regimen for asthma), nasal cromolyn sodium or sodium 
cromoglycate, nedocromil sodium, atropine, ipratropium bromide, or guaifenesin.  
x Oral/intranasal decongestants (except for short course of intranasal decongestants 
permitted for severe acute nasal blockage or during endoscopic procedures). 
x Inhaled anticholinergic medications (except for a stable regimen for subjects with chronic 
obstructive pulmonary disease [COPD]). 
x Any potent cytochrome P-450 3A4 (CYP3A4) inhibitors (eg, 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.  
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 instructed to use daily intranasal saline irrigation as background 
treatment starting from Screening through the study duration. 

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x Subjects who have been on a stable regimen of inhaled corticosteroids (not containing 
MF) or leukotriene receptor antagonists 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 2020 Global Initiative for Asthma Management and 
Prevention.[1] 
x If acute sinus infection is suspected at any time during the study, treatment with 
antibiotics or macrolides (for a maximum of 14 days) will be allowed after a clinic visit 
and according to the Investigator’s judgment. 
x For severe acute nasal blockage lasting a minimum of 3 consecutive days: a course of 
oxymetazoline nasal decongestant sprays for a maximum of 3 consecutive days and a 
total maximum of 10 days during the treatment period. [NOTE: Oxymetazoline cannot be 
used within 24 hours before CT assessments.] 
x Nonsedating oral antihistamine such as loratadine (10 mg per day) or equivalent for acute 
allergic symptoms. 
x Perennial allergic rhinitis subjects who have been on a stable regimen of a nonsedating 
oral antihistamine for a minimum of 3 months prior to the Screening visit should remain 
on the same dosage throughout the study. 
6.4.4 
Rescue Concomitant Medications and Treatment 
The following rescue medication is recommended for a worsening or uncontrolled severe CRS 
symptoms that last for a minimum of 3 days and result in the subject contacting the Investigator 
who determines an initiation of rescue treatment is necessary at any time during the study:  
x 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, or a flare-up of asthma. The dose, duration of use, and 
rationale for the use of oral corticosteroid must be recorded. 
x Sinonasal surgery as rescue treatment according to the Investigator’s recommendation. 
The type and rationale for sinonasal surgery must be recorded. 
6.5 
Removal Procedure 
Subjects will have the LYR-220 drug matrices removed bilaterally at the Week 24/EOT visit or 
earlier in an unscheduled early termination (ET) visit, if medically warranted according to the 
treating physician’s discretion (eg, require sinonasal surgery as rescue treatment or use of any 
other MF medications). The removal procedure will be performed under endoscopic 
visualization after local anesthetic and decongestants applied to each nostril. Standard surgical 
tools are used to remove LYR-220. LYR-220 is made of polymers designed to gradually soften 
over time. Care should be taken to remove LYR-220 in 1 piece or in sections should any 
disintegration of LYR-220 occur.  

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To maintain blinding through the end of the study, subjects enrolled in the sham procedure group 
will undergo a sham removal procedure either at the scheduled Week 24 visit or earlier in an 
unscheduled early termination (ET) visit if the subject requests early study product removal. 
6.6 
Treatment Compliance 
Administration and removal of LYR-220 and the sham procedure 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-220 System is a combination product comprised of a single-use applicator, preloaded 
with an anti-inflammatory drug matrix. The LYR-220 drug matrix contains mometasone furoate 
(MF), an active ingredient in multiple FDA-approved products 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-220 drug matrix is designed to gradually 
soften over time and is made of bioabsorbable polymers that have been used as components of 
approved pharmaceutical drugs and/or medical devices.  
LYR-220 has a tubular braid configuration with a uniform diamond pattern throughout. It is 
designed to be self-retaining against the mucosal tissues to allow effective drug transfer for up to 
24 weeks. The matrix is comprised of a base structure and a drug formulation layer. The base 
structure is composed of poly(L-lactide-co-glycolide) and poly(L-lactide-co-İ-caprolactone) 
elastomer to provide a 3-dimensional structure and elasticity. The drug formulation layer consists 
of the active ingredient, MF, embedded in the inactive ingredients containing poly(L-lactide-co-
İ-caprolactone) and poly(L-lactide) to control the release rate of MF. Two designs of LYR-220, 
LYR-220-32 drug matrix and LYR-220-16 drug matrix, manufactured with 32 and 16 woven 
fibers, respectively, will be assessed in this study (Figure 2). Both designs have the same 
nominal dimensions of 20 mm in diameter and 16 mm in length in the unconstrained state. 
Figure 2: Images of the Two LYR-220 Drug Matrices
7.1.2
Dosage and Administration 
Each LYR-220 drug matrix contains 7500 μg MF. LYR-220 is intended to be administered 
bilaterally into the ethmoid cavity, in which ethmoid sinuses have been removed previously by a 
bilateral ethmoidectomy, by an otolaryngologist under endoscopic visualization using the 
provided single-use applicator (Figure 3). Once administered, each LYR-220 is designed to 
gradually deliver sustained doses of MF to the inflamed mucosal tissue over a 24-week resident 
time. Bilateral placement of LYR-220 (7500 μg) is designed to deliver a total dose of 15,000 μg 
MF over the 24 weeks, or an average daily dose of 89 μg MF per person (or 45 μg MF per 
nostril).  

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Figure 3: LYR-220 Applicator Packaged with Drug Matrix (A) and Sham Applicator (B) 
 
 
 
7.2 
Drug Product Management 
7.2.1 
Packaging and Labeling 
The investigational products (LYR-220 and sham) will be packaged and labeled, as required by 
regional legislation and industry guidelines. The LYR-220 System and sham products are 
individually packaged in a foil pouch, which is sterilized and placed within a shelf carton. 
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 the study product 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 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. 

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7.2.3 
Product Traceability 
Traceability of study products shall be achieved by assigning each product package a unique 
serial/kit number as described on the label.  
7.2.4 
Product Accountability 
The Sponsor will supply sufficient quantities of LYR-220 and sham products 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. 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 Accountability Log. The Accountability Log must document the disposition of all 
investigational products 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 products that are 
associated with a malfunction, the products and all ancillary components (eg, applicator) 
remaining from the index procedure should be retained in case they need to 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. All subjects in Part 1 and Part 2 will undergo these study assessments 
per the schedule. 
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.  
Vital signs and a limited physical exam, focusing on physical appearance of head, eyes, ears, 
nose, and throat (HEENT) will be performed at Screening visit. Samples for hematology and 
chemistry will be collected at Screening and Week 25 visits.  
Nasal cavities will be assessed by endoscopy at Screening, Day 1 before the LYR-220 insertion 
procedure, and at Weeks 4, 12, 24/EOT (before LYR-220 removal), and Week 25 visits. Local 
safety evaluation of the ethmoid cavity will be performed at these visits to document presence of 
epistaxis, mucosal injury, and any other local adverse effects. On Day 1 (before LYR-220 
insertion) and at Week 25 visits, nasal swabs will be collected in ethmoid cavities to evaluate the 
impact of LYR-220 on nasal inflammatory marker level by protein and mRNA assays.  
Ophthalmologic assessments will include IOP and slit-lamp examination during Screening and at 
Week 25 visit. IOP assessment will also be performed at Week 4 and 12 visits. 
For female subjects of childbearing potential, a serum pregnancy test will be performed at the 
Screening visit and a urine pregnancy test will be performed on Day 1 prior to treatment to 
confirm eligibility for participating in the study. Additionally, a urine pregnancy test will be 
performed at Weeks 4, 12, and 24/EOT or ET visits in these female subjects. 
Plasma samples for PK will be collected from all subjects at Day 1 pre-procedure, 1 hour (±10 
minutes) post procedure on Day 1, Day 2 or 3, Day 5 or 8, and Weeks 4, 12, 16 or 20, 24/EOT, 
and Week 25 visits.  
Enrolled subjects will be asked to complete a daily ePRO questionnaire to assess the severity of 
the 4 CS of CRS (nasal blockage/obstruction/congestion, facial pain/pressure, anterior/posterior 
nasal discharge, and loss of smell). In addition, the ePRO will capture use of daily saline 
irrigation by the subjects. Subjects will also complete 2 validated CRS-specific quality of life 
questionnaires, the SNOT-22 and CRS-PRO, at Screening, on Day 1 before treatment, and at 
Weeks 2, 4, 6, 8, 12, 16, and 20, at Week 24 before matrix removal, and at Week 28/EOS. CRS-
PRO will also be assessed at Day 8 and Week 3. The PGIS will be administered on Day 1 

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(pretreatment) and at Weeks 8, 16, and 24/EOT. The PGIC will be assessed at Week 24/EOT. At 
Week 28/EOS visit, an end-of-study questionnaire will be administered.  
Ethmoid cavity opacification will be assessed by CT scans obtained during Screening (or using a 
historical scan taken within 3 months of Screening) and at Week 25 visit, unless medically 
contraindicated. Subjects will be instructed to stop use of saline rinse approximately 24 hours 
prior to the scheduled sinus CT. Daily saline irrigation should then continue following the sinus 
CT. If a subject is experiencing or recovering from a cold, acute exacerbation of nasal allergy, or 
upper respiratory tract infection at Week 25 visit, the CT assessment should be performed 4 
weeks after resolution of the adverse event. If a subject early terminates from the study or 
requires SCS or sinonasal surgery as rescue treatment during the study, every attempt should be 
made to perform the follow-up CT before subject receives the rescue treatment. 
 
 

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Table 1: Schedule of Assessments for Subjects Enrolled 
Evaluation 
Screen
ing & 
Run-In 
Proce
dure 
Day  
Treatment Stage 
Post-
Treatment 
Stage 
Visits # 
1 
2 
3 
4 
T 
T 
5 
T 
T 
6 
7/T 
8 
9 
10/T p 
Study Day/Week 
DAY -
28 
 (Day -
28 to 
Day 0)  
DAY 1 
(Day 
1) 
DAY 2 
(Day 2) 
DAY 3 
(Day 3) 
DAY 5 
(Day 5) 
DAY 8 
(Day 8) 
WK 2 
(Day  
15±1)  
WK 3 
(Day  
22±2) 
WK 4 
(Day 
29±3) 
WK 6 
(Day 
43±3) 
WK 8 
(Day 
57±3) a  
 
WK 12 
(Day 
85±3) 
WK 16 
(Day 
113±3) 
a  
WK 20 
(Day 
141±3) 
a  
WK 
24/EO
T/ET 
(Day 
169±7) 
WK 25 
(5-9 
days 
after 
EOT/E
T) 
WK 28 
(EOS) 
(25-31 
days 
after 
EOT) 
Informed Consent 
X c 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Limited Physical Exam l 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Test f 
X e 
X d,e 
 
 
 
 
 
 
X e 
 
 
X e 
 
 
X e 
 
 
Hematology/Chemistry f 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Sinus CT 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X m, n 
 
PK 
 
X d, o 
X g 
X g 
 
 
X 
 
 
X 
X g 
X d 
X 
 
Nasal Endoscopy  
X 
X i 
 
 
 
 
 
 
X i 
 
 
X i 
 
 
X d, i 
X i 
 
Ophthalmology (IOP and slit-lamp) 
X 
 
 
 
 
 
 
 
X b 
 
 
X b 
 
 
 
X m 
 
Eligibility Assessment 
X 
X d 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Nasal secretion & mucosal RNA (culture 
& cytology swabs) 
 
X d 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Run-in 
X h 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization (Part 2 study only) 
 
X d 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Insertion Procedure 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Removal Procedure 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Daily 4CS ePRO j   
X 
SNOT-22 Questionnaire j 
X r 
X d, r 
 
 
 
 
X r 
 
X r 
X r 
X r 
X r 
X r 
X r 
X d, r 
 
X r 
CRS-PRO Questionnaire j 
X s 
X d, s 
 
 
 
X s 
X s 
X s 
X s 
X s 
X s 
X s 
X s 
X s 
X d, s 
 
X s 
PGIS 
 
X d,q 
 
 
 
 
 
 
 
 
X q 
 
X q 
 
X q 
 
 
 

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Evaluation 
Screen
ing & 
Run-In 
Proce
dure 
Day  
Treatment Stage 
Post-
Treatment 
Stage 
Visits # 
1 
2 
3 
4 
T 
T 
5 
T 
T 
6 
7/T 
8 
9 
10/T p 
Study Day/Week 
DAY -
28 
 (Day -
28 to 
Day 0)  
DAY 1 
(Day 
1) 
DAY 2 
(Day 2) 
DAY 3 
(Day 3) 
DAY 5 
(Day 5) 
DAY 8 
(Day 8) 
WK 2 
(Day  
15±1)  
WK 3 
(Day  
22±2) 
WK 4 
(Day 
29±3) 
WK 6 
(Day 
43±3) 
WK 8 
(Day 
57±3) a  
 
WK 12 
(Day 
85±3) 
WK 16 
(Day 
113±3) 
a  
WK 20 
(Day 
141±3) 
a  
WK 
24/EO
T/ET 
(Day 
169±7) 
WK 25 
(5-9 
days 
after 
EOT/E
T) 
WK 28 
(EOS) 
(25-31 
days 
after 
EOT) 
PGIC 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X q 
 
 
End-of-Study Questionnaire 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Concomitant Medications/Procedures 
X 
Adverse Events k 
X 
Abbreviations: 4CS = 4 cardinal symptoms of CRS; ePRO = electronic patient-reported outcomes; T = Telephone follow-up; EOT = end of-treatment; ET = early termination; 
EOS = end-of-study; IOP = intraocular pressure; PGIC = Patient Global Impression of Change; PGIS = Patient Global Impression of Severity; PK = pharmacokinetic testing; RNA 
= ribonucleic acid; SNOT = 22-item Sino-Nasal Outcome Test; WK=week. 
a: 
Phone follow-up to collect any potential AEs and use of concomitant medications/procedures.   
b: 
IOP assessment only. 
c: 
Informed consent to be obtained before any study-related assessments occur. 
d: 
Occurs before the LYR-220/sham insertion on Day 1 or removal procedures at Week 24.  
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: 
Subjects return to clinic for PK assessment at only 1 of 2 timepoints at Visits 3 and 4. Subjects return to clinic for Visit 7 PK assessment either at Week 16 or Week 20; a 
telephone follow-up will be performed the week the subject is not returning for a PK draw.  
h: 
Subjects will start daily saline irrigation during run-in period. 
i: 
Nasal safety assessments of ethmoid cavity including epistaxis, mucosal injury, and any other adverse findings will be performed on Day 1 (before LYR-220 insertion) and 
at Week 4, 12, 24/EOT, and 25 visits. 
j: 
Daily (between 06:00:00AM and 11:59:59AM) cardinal CRS symptoms, to be recorded by the subject on ePRO questionnaire beginning at least 14 days preceding or on 
Day 1 visit (prior to randomization). 
k:  
All adverse events shall be reported after subject signs informed consent. 
l: 
A physical examination of the head, eyes, ears, nose, and throat (HEENT). 
m: 
To be performed within 5-9 days after removal procedure. 
n: 
If a subject is experiencing or recovering from a cold, acute exacerbation of nasal allergy, or upper respiratory tract infection at the Week 25/EOS visit, the CT assessment 
should be performed 4 weeks after resolution of the adverse event.   
o: 
A blood sample for PK assessment should be collected 1 hour (±10 minutes) after bilateral LYR-220 insertion. 
p: 
Week 28/EOS follow-up may be performed either as a telephone follow-up or an in-clinic visit (if subjects need to return a study supplied ePRO device). 
q: 
It is recommended that the PGIS be completed after the 4CS questionnaire. The PGIS should be completed before the PGIC. 
r: 
SNOT-22 to be recorded by the subject based on a recall period of 2 weeks (14 days) prior to visit. 
s: 
CRS-PRO to be recorded by the subject based on a recall period of 7 days prior to the visit. 

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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 rhinosinusitis  
x Asthma 
x Chronic obstructive pulmonary disease (COPD)  
x Perennial rhinitis 
x Seasonal allergic rhinitis (SAR) 
x Sensitivity to nonsteroidal 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 Ethmoidectomy 
x Polypectomy 
x Nasal surgery involving nasal turbinates 
x Functional endoscopic sinus surgery (FESS) 
x Any known history of surgery or injury that may prevent placement or retention of 
LYR-220  
8.3 
Assessment of Safety 
8.3.1 
Physical Examination 
A limited physical examination including a careful assessment of the head, eyes, ears, nose, and 
throat (HEENT), will be performed at Screening visit as specified in the Study Schedule of 
Assessment (Section 8.1). Height and weight will also be measured. Body mass index (BMI) will 
be calculated based on the measured height and weight. 
8.3.2 
Vital Signs 
Vital signs will be measured at the screening visit as specified in the Schedule of Assessments 
(Section 8.1). Vital sign measurements will include blood pressure (systolic and diastolic, mm 
Hg), and pulse rate (beats per minute), aural/oral temperature (°C or °F), and respiration rate 
(breaths per minute). All measurements will be obtained after the subject has been seated for at 
least 5 minutes.  

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8.3.3 
Laboratory Assessments 
Laboratory testing will be performed at clinic visits as specified in the Schedule of Assessments 
(Section 8.1). Any unused duplicated samples collected for the purpose of this study will be 
destroyed after the completion of the study. Testing will be performed at a central laboratory. 
8.3.3.1 
Hematology 
Samples for hematology assessments will be obtained during Screening and Week 25 visits as 
specified in the Schedule of Assessments (Section 8.1).  
Hematology assessments will include white blood cell (WBC) count and WBC differential 
(neutrophils, eosinophils, lymphocytes, monocytes, and basophils), red blood cell (RBC) count, 
hematocrit, hemoglobin, and platelet count.  
8.3.3.2 
Blood Chemistry 
Samples for blood chemistry assessments will be obtained during Screening and Week 25 visits 
as specified in the Schedule of Assessments (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.  
8.3.4 
Nasal Endoscopy Assessments 
Ethmoid cavities will be assessed by endoscopy during Screening, on Day 1 prior to LYR-220 
administration procedure, and at Week 4, 12, 24/EOT (before LYR-220 removal), and 25 visits 
as specified in the Schedule of Assessments (Section 8.1). 
Local safety evaluation of ethmoid cavity will be performed on Day 1 prior to LYR-220 
administration procedure and at Week 4, 12, 24/EOT, and 25 visits to document presence of 
epistaxis, mucosal injury, and any other adverse local observations in ethmoid cavity.  
The severity of epistaxis will be determined by the Investigator on the basis of his or her clinical 
judgment and the following definitions: 
x Mild: blood-tinged mucus, nonactive nose bleeding 
x Moderate: active nose bleeding that does not require medical intervention 
x Severe: frank nose bleeding that requires medical intervention  
The severity of mucosal injury will be determined by the Investigator on the basis of his or her 
clinical judgment and the following definitions: 
x Mild: evidence of epithelial erosion 
x Moderate: evidence of ulceration through the epithelial layer with exposed 
underneath tissue 
x Severe: perforation 

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8.3.5 
Ophthalmologic Assessments 
The ophthalmologic assessment of IOP and slit-lamp examination to identify development or 
worsening of cataract will be conducted at Screening and Week 25 visits as specified in the 
Schedule of Assessments (Section 8.1). The cataract assessment will be conducted according to 
the Simplified Cataract Grading System authored by the World Health Organization Cataract 
Grading Group. Subject’s eyes will be dilated with mydriatics following the WHO guidance for 
cataract assessment.[42] IOP may be measured using Goldmann applanation tonometer, 
noncontact tonometer, or tono-pen; however, it is recommended that the same method be used 
for consistency across serial assessments on a given subject. IOP assessment will also be 
performed at Week 4 and 12 visits. A clinically significant increase of IOP is defined as IOP in 1 
or both eyes >23 mm Hg or an increase of IOP from baseline in 1 or both eyes 10 mm Hg. 
Assessments will be conducted by an ophthalmologist/ optometrist that is blinded to the subject’s 
treatment assignment.  
8.3.6 
SCS rescue 
Oral steroids for rescue treatment of CRS or intravenous or oral steroids for another reason that 
are prescribed to the subject are to be recorded in the eCRF. All efforts should be made to 
complete the Week 25 assessments including nasal endoscopy and CT before starting treatment 
with SCS. However, the subject should continue with the study treatment and follow-up visits. 
The investigator (or designee) will record the dates and dosing information (dosage form, daily 
dose, duration, name of drug) on the appropriate page(s) of the eCRF. Indication for SCS use 
will also be captured. A course of SCS is considered continuous if treatment is separated by less 
than 7 days. 
8.3.7 
Sinonasal surgery (actual or planned) for CRS 
For subjects who have a surgery or have a scheduled date for sinonasal surgery as rescue for 
CRS, the reason (worsening signs and/or symptoms during the study), the date the surgery was 
indicated, expected or actual surgery date, and the type and outcome of surgery will be recorded 
in the eCRF. Types of sinonasal surgery include, but are not limited to, repeat FESS, balloon 
sinuplasty, turbinate reduction, septoplasty or polypectomy, or any endoscopic procedure that 
results in sinonasal tissue removal. 
If the surgery is to be performed during the study treatment period, the study treatment will be 
discontinued and all procedures/assessments for the Week 24/EOT visits will be completed prior 
to the surgery. Additionally, all efforts should be made to complete the Week 25 assessments 
including nasal endoscopy and CT prior to the surgery. The subject will be discontinued from the 
study. 
If the surgery is scheduled after the planned end of study, the investigator (or designee) should 
follow-up with the subject on the occurrence and outcome of the surgery until the time of 
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8.3.8 
Pharmacokinetic Analysis 
Blood samples for assessment of plasma PK will be collected from all subjects on 9 occasions as 
specified in the Schedule of Assessments (Section 8.1): 
x Day 1 pre-procedure  
x 1 hour (±10 minutes) post procedure on Day 1  
x Day 2 or 3  
x Day 5 or 8  
x Week 4  
x Week 12  
x Week 16 or 20 
x Week 24/EOT, and  
x Week 25 
At the Day 1 visit, the blood samples for plasma PK analysis will be collected before the LYR-
220 administration procedure and 1 hour (±10 minutes) after the procedure. At the Week 
24/EOT visit, the blood sample will be collected before the LYR-220 removal procedure. Blood 
samples may be collected at any time of the day during all the other scheduled study visits. The 
concentration of MF in plasma will be measured at a central core lab. 
8.3.9 
Explanted LYR-220 Analysis 
All removed or spontaneously dislodged LYR-220 will be collected and returned to Lyra 
Therapeutics (or designee) if allowed by the individual hospital standard operating procedures 
(SOPs). Instructions for the processing and return of removed or spontaneously dislodged LYR-
220 will be provided.  
The mass of remaining MF in LYR-220 and the molecular weights of the polymers in LYR-220 
may be measured. 
8.3.10 
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 reverified before treatment 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 at Week 4, 12, and 24/EOT visits. 
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 1 week 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 1 week after the removal procedure. Acceptable barrier 
methods include a condom and diaphragm.  
 
 

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Definition of Childbearing Potential and Highly Effective Contraceptive Methods: 
A woman is considered of childbearing potential (ie, fertile), following menarche and until 
becoming postmenopausal unless permanently sterile. Permanent sterilization methods include 
hysterectomy, bilateral salpingectomy, and bilateral oophorectomy. 
A postmenopausal state is defined as no menses for 12 months without an alternative medical 
cause. A high follicle stimulating hormone (FSH) level in the postmenopausal range may be used 
to confirm a postmenopausal 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 LYR-220 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 postpartum (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. 
8.3.11 
Adverse Events and Serious Adverse Events 
8.3.11.1 
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 CRF. All ongoing AEs that result in early termination from the 

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study or are deemed to be study 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 product, 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, clinically significant 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-220 administration procedure. 
8.3.11.2 
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 (ie, 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 8.3.11.4). Any treatment related SAE will be followed until 
resolution of the event, or until the subjects withdraw from the study. 
8.3.11.3 
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. 
8.3.11.3.1 
Relationship to Study Drug Product  
The relationship between an AE and the LYR-220 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.

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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-220 study drug product administration will be 
captured. 
8.3.11.3.2 
Relationship to Study Procedure 
The relationship between an AE and the LYR-220 administration or removal 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.
For events that are determined to be definitely or possibly related to the study LYR-220 
administration or removal procedure, additional information on the timing of the event in relation 
to the study procedure will be captured. 
8.3.11.4 
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 product or procedure 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.

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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.
8.3.11.5 
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, IB, 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 IB or prescribing information for the
registered formulation of MF or is listed at the specificity and severity that has been
observed.
8.3.11.6 
Reporting 
8.3.11.6.1 
Adverse Event Reporting 
Adverse events are to be collected from the time a subject signs the 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.  
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 (eg, clinically significant) change from baseline for that individual 
subject. If this laboratory test result is determined to be a clinically significant 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.  

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All AEs will be coded using the latest version of Medical Dictionary for Regulatory Activities 
(MedDRA) throughout the study. 
8.3.11.6.2 
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 (eg, 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.  
8.3.11.6.3 
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: 
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. 
8.3.12 
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 

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and routine safety monitoring of the study, review of serious and nonserious AEs, various data 
listings, lab results, vital signs, and other clinical data may be undertaken. Reviews of 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. 
8.4 
Assessment of Efficacy 
8.4.1 
Subject Reported Outcomes 
Subject symptoms, 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. In 
instances where the ePRO may not be available for any reason, subjects will be instructed to 
complete the PRO questionnaires using paper forms. At all clinic visits, questionnaires will be 
completed prior to any intranasal procedure or clinic assessments. 
8.4.1.1 
Chronic Rhinosinusitis Cardinal Symptom Assessment 
For assessment of the 4 CS of CRS, the ePRO will be completed by subjects on a daily basis as 
specified in the Schedule of Assessments (Section 8.1). Subjects will start recording their 
symptoms on the ePRO at least 14 days preceding the Day 1 visit. A minimum of 4 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 CS of CRS, as defined in the European Position Paper on Rhinosinusitis and Nasal Polyps 
2020[9], include nasal blockage/obstruction/congestion, facial pain/pressure, nasal discharge 
(anterior/posterior nasal drip), and reduction or loss of smell.  
Subjects will complete the daily assessment of their CS severity each morning (between 
06:00:00AM to 11:59:59AM) and rate the severity of each symptom at its worst over the past 24 
hours on a 4-point scale (Section 13.1): 
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)
8.4.1.2 
Saline Irrigation Use 
The ePRO will also be used to collect the frequency of daily saline irrigation by the subjects. 
Subjects will be instructed to stop use of saline rinse approximately 24 hours prior to the 
scheduled sinus CT. Daily saline irrigation should then continue following the sinus CT. 
8.4.1.3 
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 Assessments (Section 8.1).  

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The SNOT-22 questionnaire is a 22-item disease-specific quality of life instrument validated for 
use in CRS (Section 13.2).[37] Subjects will score the severity of their symptoms and 
social/emotional consequences of CRS on a 6-point scale over the past 2 weeks:  
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) indicate higher severity of symptoms or social/emotional 
consequences of CRS.[38] 
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. 
8.4.1.4 
Patient-Reported Outcome Measure for Chronic Rhinosinusitis (CRS-PRO) 
Questionnaire  
The ePRO will also be used to collect responses to the CRS-PRO questionnaire at the time points 
specified in the Schedule of Assessments (Section 8.1). The 12-item CRS-PRO is a new disease-
specific measure of CRS (Section 13.3).[39] It is a validated measure of CRS symptoms and was 
developed by using extensive input from CRS patients. The questionnaire assesses CRS in 3 
domains including physical symptoms, sensory impairment, and psychosocial effects. Subjects 
will score the severity of their CRS symptoms on a 5-point scale over the past 7 days, with 
higher score representing worse quality of life:  
x
0 = not at all
x
1 = a little bit
x
2 = somewhat
x
3 = quite a bit
x
4 = very much
8.4.1.5 
Patient Global Impression of Severity (PGIS) 
The ePRO will also be used to collect responses to the PGIS questionnaire at the time points 
specified in the Schedule of Assessments (Section 8.1). Subjects will be asked a single question 

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to rate their severity of CRS-related symptoms over the past 7 days on a 5-point ordinal scale: 
none, mild, moderate, severe, very severe. 
8.4.1.6 
Patient Global Impression of Change (PGIC) 
The ePRO will also be used to collect responses to the PGIS questionnaire at Week 24, as 
specified in the Schedule of Assessments (Section 8.1). The PGIC is a self-assessment of the 
subject’s overall change in CRS-related symptom severity compared to pretreatment. The PGIC 
7-point balanced scale is as follows: very much better, much better, a little better, no change, a
little worse, much worse, very much worse.
8.4.1.7 
End-of-Study Questionnaire 
At Week 28/EOS visit, subjects will complete an end-of-study questionnaire collected by the 
ePRO (Section 13.4). The questionnaire will query subjects about their general experience and 
satisfaction with their assigned study treatment. Subjects will describe their experiences by 
answering multiple-choice questions or providing narrative responses. 
8.4.2 
Ethmoid Cavity Opacification Imaging 
Ethmoid cavity opacification will be assessed by CT at the time points specified in the Schedule 
of Assessments (Section 8.1), unless medically contraindicated. The Screening CT should be 
performed anytime between the Screening and Day 1 visits. Alternatively, a historical CT scan 
can be used if done within 3 months preceding the Screening visit. The follow-up CT will be 
conducted within 5-9 days after the LYR-220 removal procedure at Week 25 visit. If a subject is 
experiencing or recovering from a cold, acute exacerbation of nasal allergy, or upper respiratory 
tract infection at the Week 25 visit, the CT assessment should be performed 4 weeks after 
resolution of the adverse event. If a subject early terminates from the study or requires SCS or 
sinonasal surgery as rescue treatment during the study, every attempt should be made to perform 
the follow-up CT before subject receives the rescue treatment. The percent opacification of 
ethmoid cavity will be evaluated by an imaging core lab.  
8.4.3 
Nasal Inflammatory Marker Levels 
Nasal inflammatory marker levels will be assessed by collecting nasal swabs at the visits 
specified in the Study Schedule of Assessments (Section 8.1). The baseline nasal swabs will be 
collected before LYR-220 administration at Day 1 visit. The follow-up nasal swabs will be 
collected at Week 25 visit. Nasal swabs will be collected from each side nasal passage to assess 
levels of T2 inflammatory markers. Two nasal swabs per side (1 for protein sample collection 
and 1 for RNA sample collection) will be collected. Nasal swabs will be collected according to 
the guidelines provided by the Sponsor.  

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9.
STATISTICAL ANALYSIS
9.1 
Sample Size 
Because the primary objective of this study is to assess the safety, tolerability, and 
pharmacokinetics of LYR-220, the sample size determination is not based on statistical power 
considerations. Up to 10 subjects will be treated in the part 1 and approximately 40 subjects will 
be treated in part 2 of the study, respectively. 
9.2 
Analysis Populations 
The following analysis sets are defined for analysis purposes: 
x
Safety analysis set: All subjects who received the study treatment. Subjects will be
analyzed according to the treatment received. This is the primary analysis set for
assessment of safety.
x
Efficacy analysis set: All subjects who received the study treatment. This is the primary
analysis set for assessment of efficacy. Subjects will be analyzed according to the
treatment they actually received.
9.3 
Disposition and Population Assignment 
Subject disposition will be summarized for all consented subjects and will include the total 
number and percentage of subjects enrolled into the study, treated, and completed the study. The 
number and percentage of subjects prematurely discontinuing from the study will be presented 
for each treatment group. Subjects who discontinue from the treatment or the study are 
categorized by reason for discontinuation; the number and percentage of subjects in each 
category will also be summarized for each treatment group. Analysis set assignment will be 
summarized by treatment group. 
9.4 
Demographic and Other Baseline Characteristics 
All demographic (age, sex, race, ethnicity, height, weight, and BMI) and baseline disease 
characteristics recorded at screening and prior to LYR-220 administration will be summarized by 
treatment group for the efficacy analysis set. Continuous data will be summarized by treatment 
group using the following descriptive statistics: the number of observations (n), mean, SD, 
median, minimum, and maximum. Categorical data will be summarized by treatment group as 
number and percentage of subjects in each category. Medical history and pregnancy test results 
will only be listed by subject. 
9.5 
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 1 concomitant medication will be presented. 

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9.6 
Safety Analyses 
All safety analyses will be performed using the safety 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 after the initiation of study treatment administration. 
Adverse events will be coded using the latest version of the Medical Dictionary for Regulatory 
Activities (MedDRA). For each study treatment, incidence rates (number and percentage of 
subjects with at least 1 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, TESAEs leading to death, and TEAEs leading to discontinuation of study treatment 
will be tabulated as number and percentage of subjects with at least 1 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 will be summarized by treatment group using descriptive statistics for 
actual value and change from baseline. Treatment-emergent abnormal and clinically significantly 
abnormal laboratory test results, ophthalmology examination findings, and nasal endoscopy 
findings will be summarized by treatment group. 
9.7 
Pharmacokinetic Analyses 
9.7.1 
Pharmacokinetic Concentrations  
PK concentration will be summarized for subjects in the Efficacy analysis set with available 
plasma MF concentration 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 LYR-220 design and actual PK
sampling time, including number (n), mean, SD, coefficient of variation (CV), median,
PLQLPXPPD[LPXPDQGWKHQXPEHURIFRQFHQWUDWLRQV//24 The “<LLOQ” values
will be set to zero based on the Beal’s method M7.[40]
9.7.2 
Pharmacokinetic Parameters 
If plasma MF levels are detectable, PK parameters of MF will be estimated using a standard 
noncompartmental PK approach based on individual plasma concentration-time data. Actual PK 
sampling times will be used in the derivation of PK parameters. Maximum concentration (Cmax) 
and time to reach maximum concentration (Tmax) will be taken directly from the observed data. 

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Total drug exposure up to the last measured concentration (AUC0-last) and the 12-hour average 
drug exposure (AUC0-12h average) will be calculated from the plasma concentrations versus time 
profiles. Descriptive statistics of these parameters will be presented by treatment group. 
9.8 
Efficacy Analyses 
All efficacy analyses will be carried out after the last subject completes the Week 28/EOS visit 
or withdraws prematurely prior to Week 28/EOS. Each efficacy analysis will be performed based 
on the Efficacy analysis set. 
9.8.1 
Efficacy Endpoint Analysis 
The efficacy endpoints are: 
x
CFBL in SNOT-22, CRS-PRO, or cardinal symptom scores
x
Time to first rescue treatment recommendation
x
Oral steroid use or sinonasal surgery
x
CFBL in bilateral percent ethmoid cavity opacification by CT at Week 25
x
CFBL in PGIS score at Weeks 8, 16, and 24
x
PGIC score at Week 24
x
Conversion to a candidate no longer requiring revision surgery
x
CFBL in biomarker level at Week 25
There will be no adjustment of the significance level for multiple comparisons across the 
endpoints. 
9.8.1.1 
CFBL in SNOT-22, CRS-PRO, PGIS, or Cardinal Symptom Scores 
Descriptive statistics (number of observations[n], mean, SD, median, minimum, and maximum) 
of the observed score and the CFBL score at each timepoint will be presented for each treatment 
group for SNOT-22, CRS-PRO, PGIS, or CS scores.  
A mixed model repeated measures (MMRM) approach will be used to compare changes from 
baseline (CFBL) between each LYR-220 group and the sham procedure group in SNOT-22, 
CRS-PRO, PGIS, and CS scores. P values ZLOOEHFRQVLGHUHGVWDWLVWLFDOO\VLJQLILFDQW An 
analysis of covariance (ANCOVA) model will be used to analyze the CT score and biomarker 
levels. 
9.8.1.1.1 
Handling of Missing Data and Data Post-Rescue Treatment 
Efficacy data collected after early termination will be included in the analysis. A last observation 
carried forward (LOCF) method will be used to impute post rescue treatment and missing data. 
Rescue treatments include SCS and/or sinonasal surgery for any reason. There will be no 
imputation for missing follow-up CT or biomarker assessments. 
9.8.1.2 
Time-to-First Recommendation of Rescue Treatment 
This efficacy endpoint is to analyze the first time a subject uses rescue treatment for worsening 
of CRS symptoms. Rescue treatment is defined as, after subject enrollment, worsening or acute 
exacerbation of CRS in a subject resulting in the treating physician reporting an escalation of 

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treatment with either systemic corticosteroids (SCS) and/or sinonasal surgery. Time to first 
recommendation of rescue treatment will be analyzed using Kaplan-Meier (K-M) method. The 
K-M estimate of median time to first recommendation of rescue treatment (if estimable) will be
presented for each treatment group. The K-M curve of time to first recommendation of rescue
treatment will be compared between each LYR-220 group and the sham procedure group using
the log-rank test.
9.8.1.3 
Oral Steroids or Sinonasal Surgery Recommendation 
The endpoint will be summarized using the percentage of subjects being recommend by treating 
physician for oral/systemic steroids (SCS) or sinonasal surgery in each treatment group. 
Comparison between each LYR-220 group and the sham procedure group will be performed 
using a Cochran-Mantel-Haenszel (CMH) test controlling for nasal polyp status. 
9.8.1.4 
CFBL in Bilateral Percent Ethmoid Cavity Opacification by CT at Week 25 
Mean CFBL in bilateral percent ethmoid cavity opacification by CT at Week 28 will be 
compared between each LYR-220 group and the sham procedure group using an ANCOVA 
model with fixed-effect terms for treatment group and nasal polyp status with baseline score as a 
covariate. 
9.8.1.5 
Conversion to A Candidate No Longer Requiring Revisions Surgery 
This responder endpoint will be summarized using the percentage of subjects that meet the 
criteria for no longer requiring revision surgery in each treatment group. Comparison between 
each LYR-220 group and the sham procedure group will be performed using the CMH test 
controlling for nasal polyp status. 
9.8.1.6 
CFBL in Nasal Inflammatory Marker Levels at Week 25 
Mean CFBL in nasal inflammatory marker levels at Week 25 will be compared between each 
LYR-220 group and the sham procedure group using an ANCOVA model with fixed-effect 
terms for treatment group and nasal polyp status with baseline score as a covariate. 
9.9 
Interim Analysis/ Study Adaptation 
An interim analysis may be performed to assist with better understanding of the study progress 
and optimal management of time and resources. Details of the interim analysis performed will be 
included in the statistical analysis plan.  
Based on feedback from study Investigators in Part 1 regarding maneuverability and ease of use 
of the LYR-220-16 matrix, the Sponsor decided to drop this treatment arm in Part 2 of the study; 
patients will be randomized 1:1 to LYR-220-32 or sham procedure control.  

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10.
REGULATORY OBLIGATIONS
10.1 
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, IRBs 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 or equivalent Investigator Statement
x
A current (ie, updated no more than 24 months prior) curriculum vitae for the
Principal Investigator and each subinvestigator listed on the FDA Form 1572 or
Investigator Statement
x
A copy of the current medical license for the investigator and each subinvestigator
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 (eg, 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
10.2 
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. 
10.3 
Ethics Committee (EC) or Institutional Review Board (IRB) Approval 
The clinical protocol and informed consent form (ICF) must have the approval of a properly 
constituted EC/IRB responsible for approving clinical studies prior to commencing the study at 
that site. Any additional approval requirement(s) of the EC/ IRB will be followed. Any 

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advertisements used to recruit subjects or any subject facing documents will also be reviewed 
and approved by the EC/IRB 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/IRB and Sponsor. Each site 
Principal Investigator will advise their EC/IRB of the progress of this clinical investigation on a 
regular basis, according to EC/IRB 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 EC/IRB and local and national 
regulations. These reports may include SAEs, withdrawal of EC/IRB or regulatory authority’s 
approval, annual progress reports, recall information, and final reports.  
10.4 
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/IRB, 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/IRB, 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 Sponsor for review and approval to assure compliance with the ICH requirements prior to 
submitting it to the EC/IRB. 
The EC/IRB-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 

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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.  
10.5 
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 EC/IRB, as required. For nonsubstantial changes (eg, 
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/IRB and, where 
appropriate, local regulatory authority can be sufficient. The version number and date of 
amendments shall be documented. 
10.6 
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/IRB. Such deviations shall be documented and 
reported to the Sponsor and the EC/IRB (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 EC/IRB.  
The investigator agrees to inform the EC/IRB 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 

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unauthorized treatment. All subjects with protocol deviations will continue to be followed for 
safety and performance assessments.  
If an investigator is found to be repeatedly noncompliant 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. 
10.7 
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 prespecified 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.  
10.8 
Data Quality Assurance 
The investigator/designees will maintain accurate source documentation as part of subject case 
histories. Electronic data capture (EDC) 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 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 SOPs. 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 provider’s pharmacovigilance department. The coding of an AE, medical 
history and concomitant medication terms will be performed by the service provider. 

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Concomitant medications will be coded using the World Health Organization (WHO) Drug 
Dictionary and AEs/medical history terms will be coded using MedDRA. 
10.9 
Record Retention 
Each investigator will maintain all records pertaining to this clinical study as required by local 
regulations, the relevant EC/IRB and the Institution. The investigator will maintain all study 
related documentation including all correspondence, records of financial interest, individual 
subject records, ICFs, 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 CRFs.  
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, 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 Research Agreement (CTRA), 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. 
10.10 
Auditing 
The investigator will make all pertinent records available including source documentation for 
inspection by their EC/IRB 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/IRB in relation to 
this clinical study, the investigator will notify the Sponsor immediately and must provide the 
Sponsor with copies of any associated correspondence (eg, EC audit reports, warning letters). 
The Sponsor will provide any necessary support in responding to regulatory authority and 
EC/IRB audit requests. 
10.11 
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/IRB is expressly permitted. The investigator agrees 

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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 CTRA.  
10.12 
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 (eg, 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. 
10.13 
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: 
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 

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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, Australian Clinical Trial Handbook, 
or other relevant national regulations, as appropriate 
Study termination and follow-up will be performed in compliance with the conditions set forth in 
ICH E6(R2) on GCP as well as 21 CFR 312.56b, Australian Clinical Trial Handbook, 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/IRB 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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11. 
CLINICAL RISK AND BENEFIT ANALYSIS 
The most common first-line therapy for CRS symptoms management is topical corticosteroids 
with adjunctive use of daily nasal saline irrigation.[10] However, inefficient drug delivery to the 
inflamed mucosal tissues[11] and poor patient compliance limit the effectiveness of such 
therapy.[12] Flare-ups and worsening inflammation or severe nasal polyps are typically managed 
with a short course (1-3 weeks) of oral corticosteroids.[8, 9] While effective initially, 
improvements are typically not sustained for longer than 3 months.[13, 14] Additionally, oral 
corticosteroids can lead to systemic side effects including mood disturbance, gastrointestinal 
issues, diabetes, cataracts, glaucoma, and osteoporosis,[15, 16] which have limited their routine 
use. Approximately 50% of patients fail medical management[17] and become potential 
candidates for functional endoscopic sinus surgery (FESS). FESS removes inflamed tissues and 
bone to open the sinonasal passages to facilitate normal sinus drainage and aeration and provide 
greater access for delivery of topical steroids. Although FESS can improve symptoms and 
quality of life, it does not correct the underlying cause of the inflammation nor obviate the need 
for continued medical management, primarily consisting of intranasal corticosteroids and nasal 
saline. Furthermore, approximately 65% of patients have recurrent symptoms post FESS within 
the first year[19] and up to 20% elect a revision surgery.[20]  
Subjects enrolled in this Phase II study will include patients who have had a prior bilateral 
ethmoidectomy, but their symptoms are recurring and not adequately controlled on medical 
management and are seeking further treatment. This may include patients who are considering an 
alternative therapy to a revision sinus surgery. The anticipated benefits over existing medical 
therapies, for subjects in this trial are local delivery of a known effective anti-inflammatory 
corticosteroid drug (mometasone furoate) to a targeted area for an extended duration of time 
without the need for daily use compliance. Subjects are expected to experience decreased 
sinonasal symptoms, which will be assessed and recorded by daily CRS cardinal symptoms, 2 
disease-specific questionnaires, SNOT-22 and CRS-PRO, and a general symptom severity 
questionnaire, the PGIS (Section 8.4.1 Subject Reported Outcomes).  
Although there is no prior human experience with LYR-220 drug matrices for treating adult CRS 
patients who have had a prior bilateral ethmoidectomy, Lyra Therapeutics has previously 
developed LYR-210 (2500 ȝJ and 7500 ȝJ) drug matrices for treating adult CRS patients who 
have failed previous medical management but have not undergone FESS. The LYR-210 drug 
matrix is designed for bilateral placement and retention of the drug matrices in undisrupted 
middle meatuses for 24 weeks, compared to LYR-220 drug matrices that are placed bilaterally in 
the ethmoid cavities. The LYR-ȝJGUXJPDWULFHVDUHIRUPXODWHGZLWKLGHQWLFDO
bioresorbable polymers, drug dose, and similar in vitro drug release kinetics to LYR-210 (7500 
ȝJGUXJPDWUL[ The completed Phase I study was to evaluate the safety of LYR-210 in adult 
CRS patients receiving LYR-210 (2500 μg) drug matrices bilaterally. 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 

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minimal and not statistically significant. No subject had intraocular hypertension (IOP >21 mm 
Hg) 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. The completed Phase II study is to evaluate the safety and efficacy of LYR-210 in 
adult CRS patients receiving LYR-210 (2500 μg) drug matrices, LYR-210 (7500 μg) drug 
matrices, or control in a 1:1:1 ratio. The most frequent local nasal AE reported in the 3 study 
groups was epistaxis; 4, 3, and 2 patients reported epistaxis in the LYR-210 (2500 μg), LYR-210 
(7500 μg), and control groups, respectively. Eight of the 9 epistaxis events were reported as 
mild; only 1 epistaxis event was reported as moderate in severity. None of the subjects in this 
study had a clinically significant increase of IOP. Only 1 subject in the control group reported a 
higher grade of nuclear cataract at Week 24 that was deemed abnormal not affecting vision and 
reported as an adverse event by the investigator. There was no significant decrease of morning 
serum cortisol levels at Week 4, 12, and 24. No AEs indicative of adrenal insufficiency were 
reported (Refer to the LYR-220 IB). 
The safety of the active ingredient in LYR-220, mometasone furoate, has been demonstrated 
across a range of commercially approved nasal and oral medication dosage forms including 
Nasonex®[21], Asmanex® Twisthaler®[22], Sinuva™[24] and PropelTM[23] 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. The systemic safety of the 
7500-μg dose MF in CRS patients has been demonstrated in the LYR-210 clinical studies. The 
MF systemic exposure in surgically naïve CRS patients that received LYR-210 (7500 μg) 
bilaterally is generally within the steady state exposure range observed in patients with asthma 
that received 400 μg BID Asmanex® Twisthaler® (Refer to the LYR-220 IB).  
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[41].   
Risks Analysis 
Potential risks to the trial subjects are similar to those associated with current therapies using 
local or systemic delivery of MF and endoscopic procedures. More detailed information 
regarding clinical safety data can be found in the IB. 
In the Phase I clinical study of LYR-210 (2500 μg) drug matrix, the most common (ie, occurred 
in more than 1 subject) treatment-emergent adverse events (TEAEs) that are related to study 
treatment were facial pain, nasopharyngitis, sinusitis, upper respiratory tract infection, nasal 
discomfort, and nasal odor. All these events were considered to be nonserious, mild or moderate 
in severity, and anticipated risks related to study treatment. In the Phase II clinical study of LYR-
210, the most common TEAEs that are related to study treatment reported in the LYR-210 (2500 

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μg) group were epistaxis and rhinorrhoea; in the LYR-210 (7500 μg) group was rhinitis; and in 
the control group was headache. All these events were considered to be nonserious and 
anticipated risks related to study treatment (Refer to the LYR-220 IB). 
The possible risks and the highest incidence rates reported in clinical studies of similar products 
and/or LYR-210 clinical studies that are related to endoscopic procedures were procedural 
headache, epistaxis, facial pain, nasal congestion, nasal discomfort, parosmia, post procedural 
discomfort, and presyncope (Refer to the LYR-220 IB).  
Subjects will be closely monitored as part of the trial according to the MMP, which defines in 
detail objectives, scope and roles and responsibilities of each team member involved (Section 
8.3.12 Safety Monitoring). Safety monitoring will be followed strictly in accordance with the 
study MMP.  
Extensive inclusion and exclusion criteria will also apply (Sections 5.3 Inclusion Criterion and 
5.4 Exclusion Criterion) for which both the risks with MF and endoscopic 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).   
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 (eg, brain abscess, related problems with eyes or central nervous 
system) or a history/diagnosis (in either eye) of glaucoma or ocular hypertension (IOP >21 mm 
Hg) 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 5 Warnings and Precautions of the prescribing 
information of Nasonex®).  
Subjects with obstruction, moderate-to-severe adhesion/synechiae, severe scarring or residual 
ethmoid cells within ethmoid cavity or resected and degenerated middle turbinate preventing 
proper placement or retention of LYR-220 will also be excluded.  
Strict subject withdrawal/discontinuation criteria will also apply (Section 4.3 Discontinuation of 
Study Subjects) including any 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 surgical intervention to manage their CRS symptoms. 
Prior and concomitant medications criteria are specified (Sections 6.4.2 Prohibited Concomitant 
Medications and 6.4.3 Permitted Concomitant Medications) to avoid confounding the safety, 

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pharmacokinetics, and efficacy assessments of LYR-220. Specific rescue medications are 
recommended for worsening of CRS symptoms that last for a minimum of 3 days and resulted in 
the subject contacting the Investigator (Section 6.4.4 Rescue Concomitant Medications).  
In the Phase I and Phase II clinical studies of LYR-210, no AEs were associated with drug 
matrix dislodgements. In this study, if spontaneous dislodgement of LYR-220 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, or subject requests matrix removal from the remaining side of the nose, or 
matrices spontaneously dislodged from both sides of the nose (Section 4.1.2 Treatment Stage).  
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 I and Phase II clinical results of LYR-210 and the safety assessments and measures 
implemented in this clinical trial, the potential benefits of LYR-220 outweigh the potential 
associated risks and support conducting the proposed Phase II clinical trial.  

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13.
APPENDICES
13.1 
CRS Cardinal Symptoms (CS) Questionnaire (Daily ePRO) [SAMPLE] 
13.2 
22-Item Sino-Nasal Outcome Test (SNOT-22) [SAMPLE]
13.3 
Patient-Reported Outcome Measure for Chronic Rhinosinusitis (CRS-PRO) 
Questionnaire [SAMPLE] 
13.4 
Patient Global Impression of Severity (PGIS) Scale [SAMPLE] 
13.5 
Patient Global Impression of Change (PGIC) Scale [SAMPLE] 
13.6 
LYR-220 End-of-Study Questionnaire [SAMPLE] 
13.7 
Summary of Protocol Changes