A Phase 2a, Single-Blind, Placebo-Controlled, Parallel-Group Study to Assess Safety, Tolerability, and Pharmacokinetics of Brensocatib Tablets in Adults With Cystic Fibrosis
Phase: PHASE2
Conditions: Cystic Fibrosis
Sponsor: Insmed Incorporated

Official Title: A Phase 2a, Single-Blind, Placebo-Controlled, Parallel-Group Study to 
Assess Safety, Tolerability, and Pharmacokinetics of Brensocatib 
Tablets in Adults With Cystic Fibrosis 
NCT Number: NCT05090904 
Document Dates: Protocol Version 3.0: 26-July-2022 

Signature Page for INS1007-211 Protocol Amendment No. 2
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Clinical Development
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Version 3.0, 26 JUL 2022 
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CLINICAL STUDY PROTOCOL 
A Phase 2a, Single-Blind, Placebo-Controlled, Parallel-Group Study to Assess 
Safety, Tolerability, and Pharmacokinetics of Brensocatib Tablets in Adults With 
Cystic Fibrosis 
Protocol Number: 
INS1007-211  
Version Number: 
3.0 
Amendment Number: 
2 (global) 
Content Final Date: 
26 JUL 2022 
Compound: 
Brensocatib (INS1007) 
Brief Title: 
A Safety, Tolerability, and Pharmacokinetic Study of 
Brensocatib in Adult Participants With Cystic Fibrosis 
Study Phase: 
2a 
Sponsor Name: 
Insmed Incorporated 
Legal Registered Address: 
700 US Highway 202/206 
Bridgewater, NJ 08807-1704 
USA 
Manufacturer: 
Insmed Incorporated 
Regulatory Agency 
Identifier Number(s): 
IND: 133790 

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Protocol Amendment Summary of Changes 
 
DOCUMENT HISTORY 
Document 
Date 
Version 3.0, Amendment 2 (global) 
26 JUL 2022 
Version 2.0, Amendment 1 (global) 
01 JUL 2021 
Version 1.0, Original Protocol 
05 FEB 2021 
Version 3.0, Global Amendment 2: 26 JUL 2022 
This amendment is considered to be substantial. 
Overall Rationale for the Amendment:  
The primary driver for the changes in the protocol amendment is to align the study to the cystic 
fibrosis population at large with regards to the proportion of patients treated with cystic fibrosis 
transmembrane conductance regulator (CFTR) modulators, which is considered a cornerstone of 
their treatment (van der Meer et al., 2021), (CF Foundation Registry, 2020).  
Grammatical and typographical errors were corrected throughout the document.  
The summary of major changes in this amendment, compared to Amendment 1 of the protocol, 
is shown below:  
Description of Change 
Brief Rationale 
Section Number 
Senior Director, Clinical 
Operations updated 
Personnel change 
Important Contact Information 
Amended trial design as 
follows: 
• 
CFTR non-modulator strata 
definition revised to include 
participants who have either 
never previously received 
CFTR modulators or have 
not been administered 
CFTR modulators within 
30 days prior to Screening 
(visit 1) and will not receive 
them during the study 
• 
Revised the number of 
participants randomized to 
each strata to 5 participants 
(CFTR modulator stratum) 
To align the study to the cystic 
fibrosis population at large with 
regards to the low proportion of 
patients (approximately only 
14% of the eligible population) 
who are not prescribed a CFTR 
modulator 
Section 1.1 
Section 1.2 
Section 4.1  
Table 1 
Section 5  

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Description of Change 
Brief Rationale 
Section Number 
and 2 participants 
(non-modulator stratum)  
• 
Revised the number of 
participants randomized to 
the placebo cohort to 
3 participants (CFTR 
modulator stratum) and 
1 participant (non-modulator 
stratum) 
• 
Revised the overall number 
of study participants to 
approximately 25 to 
34 participants 
Updated sputum sample 
collection for microbiology to 
include a sample collection at 
the Early Discontinuation visit 
Omission from initial sampling 
collection schedule 
Section 1.3  
Table footnote a updated to state 
the Pharmacokinetic (PK) 
sampling window permitted for 
Visit 7 (from the PK Sampling 
Schedule in Section 1.3.1)  
To clarify study procedure 
Section 1.3  
 
Footnote added for the 
pharmacodynamic (PD) sample 
collection description to confirm 
that the defined PK sampling 
timepoint windows do not apply 
to PD sample collections 
To clarify study procedure  
Section 1.3.1  
Updated details that participants 
must begin the study at the start 
of either their on-treatment or 
off-treatment cycled antibiotic 
regimen (previously referred to 
their inhaled antibiotic regimen) 
Cycled antibiotic regimen used 
to cover the option that 
participants may be on inhaled 
or antibiotic regimens. 
Section 4.1.2 
Section 6.8 
Section 1.2 
Updated exclusion criterion 17 
to include participants who are 
expected to have periodontal 
disease-related procedures 
To align with changes made to 
the monitoring of suspected 
periodontitis/gingivitis (adverse 
event of special interest) 
Section 5.2 

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Description of Change 
Brief Rationale 
Section Number 
within the study period (as well 
as those who are under active 
treatment for periodontal 
disease) 
Updated details of 
randomization for CFTR 
modulator and non-modulator 
strata 
To align the study to the cystic 
fibrosis population at large with 
regards to the low proportion of 
patients (approximately only 
14% of the eligible population) 
who are not prescribed a CFTR 
modulator 
Section 6.3  
Updated reporting details such 
that any clinical signs and 
symptoms associated with an 
overdose should be reported via 
the SAE form within 24 hours of 
awareness, even if no 
seriousness criteria for the 
events are met 
To align with updated reporting 
procedures 
Section 6.7  
Revision to PD sample 
collection such that sputum 
sample collection will be 
attempted on all participants, but 
sputum sample collection will 
not be required for participants 
who cannot provide sputum 
Although sputum collection is 
important to the exploratory PD 
analysis, in light of the potential 
challenges obtaining an 
adequate sample due to the 
concomitant administration of 
CFTR modulators, sputum 
sample collection will be 
attempted on all participants but 
not required for participants who 
cannot provide sputum 
Section 8  
Section 1.3 
Updated the monitoring details 
to cover cases of suspected 
periodontitis/gingivitis reported 
during the study whereby 
participants should be referred 
to a dentist/periodontist for 
evaluation, diagnosis, and 
treatment 
As an adverse event of special 
interest, cases of suspected 
periodontitis/gingivitis will be 
monitored and referred for 
evaluation 
Section 8.2.7.2 

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Description of Change 
Brief Rationale 
Section Number 
Clarification that the 
administration of a 
bronchodilator as part of a 
chronic and stable regimen is 
not prohibited 
To clarify study procedure 
Section 8.8.1  
Revisions to sample size 
determination to account for the 
trial design changes, including 
the number of participants 
randomized 
To align the study to the cystic 
fibrosis population at large with 
regards to the low proportion of 
patients (approximately only 
14% of the eligible population) 
who are not prescribed a CFTR 
modulator 
Section 9.2 
Table 5  
Updated details of exploratory 
endpoint analyses to include 
analysis by treatment group 
within strata (CFTR modulator 
and non-modulator, pooled data 
across all dose levels) 
Proposed change due to the 
anticipated smaller number of 
participants in the CFTR 
non-modulator stratum  
Section 9.4.1  
Section 9.4.4 
Clarification that no formal 
interim analysis is planned 
To clarify study procedure 
Section 9.5  
Liver safety suggested actions 
and stopping rules updated from 
Hy’s Law details to the Council 
for International Organizations 
of Medical Sciences (CIOMS) 
Drug-Induced Liver Injury 
(DILI) guidelines (CIOMS, 
2020) 
Updated in line with Sponsor’s 
protocol template and agreed 
use of stopping rule criteria as 
defined in the CIOMS DILI 
guidelines. 
Section 10.6  
Summary of changes for Global 
Amendment 1 (dated 
01 Jul 2021) moved to the 
Protocol Amendment History 
(Appendix 7)  
Placement of previous protocol 
amendments  
Section 10.7  
 
 
 

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TABLE OF CONTENTS 
CLINICAL STUDY PROTOCOL ..................................................................................................1 
Important Contact Information ........................................................................................................2 
Protocol Amendment Summary of Changes ....................................................................................3 
TABLE OF CONTENTS .................................................................................................................7 
LIST OF TABLES .........................................................................................................................11 
ABBREVIATIONS .......................................................................................................................12 
1. 
PROTOCOL SUMMARY ..........................................................................................15 
1.1. 
Synopsis ......................................................................................................................15 
1.2. 
Study Schema .............................................................................................................19 
1.3. 
Schedule of Assessments and Procedures ..................................................................20 
1.3.1. 
PK, PD, and ECG Sampling Schedule .......................................................................23 
2. 
INTRODUCTION ......................................................................................................25 
2.1. 
Background .................................................................................................................25 
2.2. 
Study Rationale ...........................................................................................................27 
2.3. 
Benefit/Risk Assessment ............................................................................................28 
2.3.1. 
Benefits .......................................................................................................................28 
2.3.2. 
Risks ...........................................................................................................................29 
2.3.3. 
Overall Benefit: Risk Conclusions .............................................................................29 
3. 
OBJECTIVES AND ENDPOINTS ............................................................................31 
4. 
STUDY DESIGN .......................................................................................................33 
4.1. 
Overall Design ............................................................................................................33 
4.1.1. 
Screening Period .........................................................................................................35 
4.1.2. 
Treatment Period ........................................................................................................35 
4.1.2.1. 
Day 1 (Baseline) .........................................................................................................35 
4.1.2.2. 
Day 2, Day 14, and Day 28 .........................................................................................35 
4.1.3. 
Follow-Up Period .......................................................................................................35 
4.1.4. 
Decision to Dose Brensocatib 65 mg ..........................................................................36 
4.1.5. 
Safety Review Committee ..........................................................................................36 
4.2. 
Scientific Rationale for Study Design ........................................................................36 
4.3. 
Justification for Dose ..................................................................................................37 
4.4. 
End of Treatment Definition .......................................................................................37 

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4.5. 
End of Study Definition ..............................................................................................38 
5. 
STUDY POPULATION .............................................................................................39 
5.1. 
Inclusion Criteria ........................................................................................................39 
5.2. 
Exclusion Criteria .......................................................................................................40 
5.3. 
Lifestyle Considerations .............................................................................................43 
5.4. 
Screen Failures ............................................................................................................43 
5.5. 
Criteria for Temporarily Delaying Administration of Investigational Product ..........43 
6. 
INVESTIGATIONAL PRODUCT AND CONCOMMITANT THERAPY .............44 
6.1. 
Investigational Product Administration ......................................................................44 
6.2. 
Preparation/Handling/Storage/Accountability ............................................................45 
6.3. 
Measures to Minimize Bias: Randomization and Blinding ........................................46 
6.4. 
Study Drug Compliance .............................................................................................46 
6.5. 
Dose Modification ......................................................................................................47 
6.6. 
Continued Access to Investigational Product After the End of the Study ..................47 
6.7. 
Overdose .....................................................................................................................47 
6.8. 
Concomitant Therapy .................................................................................................47 
6.8.1. 
Rescue Medicine .........................................................................................................48 
6.8.2. 
Dose Interruption ........................................................................................................48 
6.8.3. 
Prohibited Medications ...............................................................................................48 
7. 
DISCONTINUATION OF STUDY DRUG AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ..................................................................49 
7.1. 
Discontinuation of Study Drug ...................................................................................49 
7.1.1. 
QTc Stopping Criteria .................................................................................................49 
7.1.2. 
Pregnancy ...................................................................................................................49 
7.1.3. 
Participant Discontinuation/Withdrawal From the Study ...........................................49 
7.2. 
Lost to Follow up ........................................................................................................50 
8. 
STUDY ASSESSMENTS AND PROCEDURES ......................................................51 
8.1. 
Safety Assessments .....................................................................................................51 
8.1.1. 
Physical Examinations ................................................................................................51 
8.1.2. 
Vital Signs ..................................................................................................................51 
8.1.3. 
12-Lead Electrocardiograms .......................................................................................51 
8.1.4. 
Clinical Safety Laboratory Assessments ....................................................................52 
8.1.5. 
Estimated Glomerular Filtration Rate .........................................................................53 

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8.1.6. 
Pregnancy Testing and Contraception ........................................................................53 
8.2. 
Adverse Events, Serious Adverse Events, and Other Safety Reporting .....................54 
8.2.1. 
Time Period and Frequency for Collecting AE and SAE Information .......................54 
8.2.2. 
Method of Detecting AEs and SAEs ..........................................................................54 
8.2.3. 
Follow-Up of AEs and SAEs ......................................................................................55 
8.2.4. 
Regulatory Reporting Requirements for SAEs ...........................................................55 
8.2.5. 
Pregnancy ...................................................................................................................55 
8.2.6. 
Cardiovascular and Death Events ...............................................................................56 
8.2.7. 
Adverse Events of Special Interest .............................................................................56 
8.2.7.1. 
Hyperkeratosis ............................................................................................................56 
8.2.7.2. 
Periodontitis/Gingivitis ...............................................................................................57 
8.2.7.3. 
Other Infections ..........................................................................................................57 
8.3. 
Pharmacokinetic Assessments ....................................................................................57 
8.3.1. 
PK Sample Collection .................................................................................................57 
8.3.2. 
PK Analysis ................................................................................................................57 
8.3.3. 
Pharmacokinetic and Pharmacodynamic Evaluations ................................................58 
8.4. 
Pharmacogenomics .....................................................................................................58 
8.5. 
Biomarkers ..................................................................................................................58 
8.6. 
Sputum Assessments ..................................................................................................59 
8.7. 
Medical Resource Utilization and Health Economics ................................................59 
8.8. 
Efficacy Assessments .................................................................................................59 
8.8.1. 
Spirometry ..................................................................................................................59 
8.8.2. 
Cystic Fibrosis Questionnaire – Revised ....................................................................60 
9. 
STATISTICAL CONSIDERATIONS .......................................................................61 
9.1. 
Statistical Hypotheses .................................................................................................61 
9.2. 
Sample Size Determination ........................................................................................61 
9.3. 
Analysis Sets ...............................................................................................................62 
9.4. 
Statistical Analyses .....................................................................................................63 
9.4.1. 
General Considerations ...............................................................................................63 
9.4.2. 
Primary Endpoint ........................................................................................................63 
9.4.3. 
Secondary Endpoints ..................................................................................................64 
9.4.4. 
Exploratory Endpoints ................................................................................................64 

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9.4.5. 
Safety Analysis ...........................................................................................................64 
9.4.5.1. 
Adverse Events ...........................................................................................................65 
9.4.5.2. 
Clinical Laboratory Tests ...........................................................................................65 
9.4.5.3. 
Vital Signs ..................................................................................................................65 
9.4.5.4. 
Physical Examination .................................................................................................66 
9.4.5.5. 
Electrocardiogram .......................................................................................................66 
9.5. 
Interim Analysis ..........................................................................................................66 
10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS ..................................................................................................67 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations ....................67 
10.1.1. 
Regulatory and Ethical Considerations ......................................................................67 
10.1.2. 
Protocol Deviations ....................................................................................................67 
10.1.3. 
Public Health Emergency Situations ..........................................................................68 
10.1.3.1. 
Continuation or Suspension of the Study ...................................................................68 
10.1.4. 
Financial Disclosure ...................................................................................................69 
10.1.5. 
Informed Consent Process ..........................................................................................69 
10.1.6. 
Protection of Participant Identification and Confidentiality .......................................70 
10.1.7. 
Data Protection ...........................................................................................................70 
10.1.8. 
Committees Structure .................................................................................................71 
10.1.9. 
Dissemination of Clinical Study Data ........................................................................71 
10.1.10. 
Data Quality Assurance ..............................................................................................71 
10.1.10.1. Data Collection ...........................................................................................................72 
10.1.10.2. Study Monitoring ........................................................................................................72 
10.1.10.3. Audits and Inspections ................................................................................................72 
10.1.10.4. Study Record Retention ..............................................................................................73 
10.1.10.5. Source Documents ......................................................................................................73 
10.1.11. 
Study Files and Materials ...........................................................................................73 
10.1.12. 
Use of Stored Samples and Data ................................................................................74 
10.1.13. 
Disposition of Stored Samples and Data ....................................................................74 
10.1.14. 
Study and Site Start and Closure ................................................................................74 
10.1.14.1. First Act of Recruitment .............................................................................................75 
10.1.14.2. Study/Site Termination ...............................................................................................75 
10.1.15. 
Protocol Amendments ................................................................................................75 

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10.1.16. 
Financing and Insurance .............................................................................................76 
10.1.16.1. Finances ......................................................................................................................76 
10.1.16.2. Reimbursement, Indemnity, and Insurance ................................................................76 
10.1.16.3. Participant Reimbursement, Liability and Insurance ..................................................76 
10.1.17. 
Publication Policy .......................................................................................................76 
10.2. 
Appendix 2: Clinical Laboratory Tests .......................................................................77 
10.3. 
Appendix 3: AEs and SAEs: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting ........................................................................77 
10.3.1. 
Definition of AE .........................................................................................................77 
10.3.2. 
Definition of SAE .......................................................................................................79 
10.3.3. 
Recording and Follow-Up of AE and/or SAE ............................................................79 
10.3.4. 
Reporting of SAEs ......................................................................................................81 
10.4. 
Appendix 4: Contraceptive and Barrier Guidance ......................................................83 
10.5. 
Appendix 5: Sputum Induction Guidelines ................................................................84 
10.6. 
Appendix 6: Liver Safety: Suggested Actions and Follow-Up Assessments .............87 
10.6.1. 
Prohibited Medications ...............................................................................................88 
10.7. 
Appendix 7: Protocol Amendment History ................................................................89 
11. 
REFERENCES ...........................................................................................................93 
 
LIST OF TABLES 
Table 1: 
Participant Randomization Scheme by Dose Cohort and CFTR Modulator 
Status ...........................................................................................................................34 
Table 2: 
Investigational Product for Study INS1007-211 ........................................................45 
Table 3: 
Clinical Laboratory Parameters ..................................................................................52 
Table 4: 
Pharmacokinetic Parameters .......................................................................................58 
Table 5: 
95% CIs for Values of Inter-Participant CV(%) of the AUC0-24 and Cmax GM 
in Each Actively Treated Cohort ................................................................................62 
Table 6: 
95% CIs for Values of Inter-Participant CV(%) of the AUC0-24 and Cmax GM 
for Each Stratum Within Each Actively Treated Cohort ............................................62 
 
 

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ABBREVIATIONS  
Abbreviation  
Definition 
AE 
adverse event 
AESI 
adverse event of special interest 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil account 
ARDS 
acute respiratory distress syndrome 
AST  
aspartate aminotransferase 
ATS 
American Thoracic Society 
AUC 
area under the concentration-time curve 
AUC0-∞  
AUC from time 0 to infinity 
AUC0-24 
AUC from time 0 to 24 hours postdose 
AUClast 
AUC from time 0 to the last timepoint with measurable concentration 
BCRP 
breast cancer resistance protein 
BID 
twice a day 
CatG 
cathepsin G 
CF 
cystic fibrosis 
CFQ-R 
Cystic Fibrosis Questionnaire-Revised 
CFTR 
cystic fibrosis transmembrane conductance regulator 
CI 
confidence interval 
CKD-EPI 
Chronic Kidney Disease Epidemiology 
CL/F 
apparent total clearance of drug from plasma after extravascular administration 
Cmax 
maximum plasma concentration 
Cmin 
minimum plasma concentration 
Ctrough 
plasma concentration before the next dose 
COVID-19 
coronavirus disease 2019 
CRF 
case report form 
CRO 
contract research organization 
CTCAE 
Common Terminology Criteria for Adverse Events 
CV 
percent coefficient of variation 
CYP 
cytochrome P450 
DLT 
dose limiting toxicity 
DPP1 
dipeptidyl peptidase 1 
ECG  
electrocardiogram 

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Abbreviation  
Definition 
EDC 
electronic data capture 
eCRF 
electronic case report form 
eGFR 
estimated glomerular filtration rate 
EOS 
End of Study 
EOT 
End of Treatment 
ERS 
European Respiratory Society 
FDA 
Food and Drug Administration 
FEV1 
forced expiratory volume in 1 second 
FEF(25-75%) 
forced expiratory flow between 25% and 75% of forced vital capacity 
FSH 
follicle stimulating hormone 
FVC 
forced vital capacity 
GM 
geometric mean 
HBcAb 
hepatitis B core antibody 
HBsAb 
hepatitis B surface antibody 
HBsAg 
hepatitis B surface antigen 
HIV 
human immunodeficiency virus 
HRQOL 
health-related quality of life 
IC50 
concentration of a drug causing half-maximal inhibitory effect 
ICF 
informed consent form 
ICH 
International Council for Harmonisation  
IMP 
investigational medicinal product 
IRB 
Institutional Review Board 
IWRS 
Interactive Web Response System 
MATE 
multidrug and toxin extrusion protein  
MedDRA 
Medical Dictionary for Regulatory Activities 
MTD 
maximum tolerated dose 
NCFBE 
non-cystic fibrosis bronchiectasis 
NCI 
National Cancer Institute 
NE 
neutrophil elastase 
NOAEL 
no-observed-adverse-effect level 
NSAID 
nonsteroidal anti-inflammatory drug 
NSP 
neutrophil serine protease 
OAT 
organic anion transporters 
OATP 
organic anion-transporting polypeptide  

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Abbreviation  
Definition 
OCT 
organic cation transporter 
PD 
pharmacodynamic(s) 
PE 
pulmonary exacerbation 
PEFR 
peak expiratory flow rate 
PFT 
pulmonary function test 
Pgp 
P-glycoprotein 
PK 
pharmacokinetic(s) 
PLS 
Papillon-Lefèvre syndrome 
ppFEV1 
percent predicted forced expiratory volume in 1 second 
PR3 
proteinase 3 
PT 
preferred term 
QD 
once daily 
QTc 
corrected QT interval 
QTcF 
corrected QT interval by Fridericia’s formula 
Rac(AUC) 
accumulation ratio for AUC 
Rac(Cmax) 
accumulation ratio for Cmax 
ROS 
reactive oxygen species 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SoA 
schedule of assessments and procedures 
SOC 
System Organ Class 
SpO2 
oxygen saturation 
SRC 
Safety Review Committee 
SUSAR 
suspected unexpected serious adverse reaction 
t½  
elimination half-life 
TB 
tuberculosis 
TEAE 
treatment-emergent adverse event 
tmax 
time to maximum plasma concentration 
ULN 
upper limit of normal 
US 
United States 
Vd/F 
apparent volume of distribution 
WOCBP 
women of childbearing potential 

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Overall Design: 
This is a Phase 2a, single-blind, randomized, placebo-controlled, parallel-group, multiple-dose 
study to assess the PK, PD, and safety of brensocatib 10, 25, and 40 mg once daily (QD) in 
participants with CF. Following review of PK and safety data by a Safety Review Committee 
(SRC; Section 4.1.5), and provided that the SRC deems it appropriate to administer the next 
dose, a cohort of participants will receive brensocatib 65 mg QD on the same schedule as the 
previous cohorts. A tablet formulation of brensocatib 65 mg is not yet available; therefore, 
participants assigned to the 65 mg dose cohort will receive 1 tablet of brensocatib 25 mg and 
1 tablet of brensocatib 40 mg. 
A figure of the study schema is presented in Section 1.2. 
Overall, the study will enroll approximately 25 to 34 participants. The first three brensocatib 
dose cohorts (10 mg, 25 mg, and 40 mg QD) will enroll approximately 7 participants each, and 
the placebo cohort will enroll approximately 4 participants. For the active treatment dose 
cohorts, there will be 2 strata: approximately 5 participants who have previously received and 
will continue to receive cystic fibrosis transmembrane conductance regulator (CFTR) modulators 
as concomitant medication (CFTR modulator stratum), and approximately 2 participants who 
have either never previously received CFTR modulators or have not been administered CFTR 
modulators within 30 days prior to Screening (visit 1) and will not receive CFTR modulators 
during the study (non-modulator stratum). For the placebo cohort, approximately 3 participants 
will be randomized into the CFTR modulator stratum and 1 participant in the non-modulator 
stratum. 
Each cohort will enroll participants in a 5:1 ratio (active : placebo) for the CFTR modulator 
stratum. For the non-modulator stratum, approximately 6 participants will be randomized to 
receive active treatment (10 mg, 25 mg, and 40 mg brensocatib) and approximately 1 participant 
to placebo.  
If there are no safety issues observed in the first 3 dose cohorts, a 65 mg dose cohort will be 
similarly randomized: 7 participants (5 participants CFTR modulator and 2 participants 
non-modulator stratum) in active treatment and 2 participants in placebo (1 participant each in 
the CFTR modulator and non-modulator strata), increasing the sample size from approximately 
25 to 34 participants. 
Including the Screening (up to 28 days), Treatment (28 days), and Follow-Up Period (28 days), 
the study participation duration is expected to be 84 days or less. At the EOS (End of Study), all 
ongoing adverse events (AEs) will be assessed by the investigators whether they are resolved and 
stable or not clinically significant. Any study-related safety issues or serious events that extend 
past Study Day 56 (EOS) will be followed to resolution. 
Study drug will be administered to the participant by the study center staff on Day 1 (Baseline), 
and at all in clinic visits after Day 1 (Days 2, 14, and 28). On days when there is no in-clinic 
visit, participants will self-administer study drug at home. 
An SRC will review safety and PK data of completed cohorts exposed to brensocatib 10, 25, and 
40 mg QD in an unblinded manner to determine whether brensocatib has an acceptable safety 
and PK profile and can be escalated to the 65 mg dose as planned. 
The purpose, function, and conduct of the SRC are further described in Section 4.1.5.  

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The structure of the SRC is described in Section 10.1.8.  
Brief Summary: 
Study INS1007-211 is designed to evaluate the PK of brensocatib in participants with CF 
(primary objective), and consists of a 28-day Screening Period, a 28-day Treatment Period (visits 
at Days 1, 2, 14, and 28), and a 28-day Follow-Up Period (visits at Days 29, 35, and 56), for a 
total study duration of 84 days or less.  
Eligible participants will be randomized to receive brensocatib 10, 25, or 40 mg or placebo, 
administered QD for 28 days. Approximately 25 participants will be randomized for the first 
3 dose cohorts: 7 participants per active treatment dosing cohort (5 CFTR modulator: 
2 non-modulator participants), and a total of 4 participants assigned to receive placebo (3 CFTR 
modulator: 1 non-modulator participant[s]). If there are no safety issues with the first 3 dose 
cohorts (brensocatib 10, 25, and 40 mg), a fourth cohort (65 mg) will be added, with the same 
active treatment allocation rules used in the first 3 cohorts (5 CFTR modulator: 2 non-modulator 
participants) and 2 participants randomized to receive placebo (1 CFTR modulator: 
1 non-modulator participant), increasing the sample size from approximately 25 to 
34 participants.  
The primary PK endpoints are Cmax, Tmax, AUC0-24 and t1/2 on Day 1 and Day 28. A secondary 
analysis of dose-dependency will be performed based on AUClast, AUC0-24 and Cmax for Day 1 
and Day 28. Additional PK parameters, such as AUClast, AUCinf, CL/F, Vd/F, Cmin, Ctrough, 
Rac(AUC) and Rac(Cmax), will be determined when data permit. The definition of the PK parameters 
can be found in the abbreviation list and in PK sections.   
The primary safety endpoint is the frequency of treatment-emergent adverse events.  
The Schedule of Assessments and Procedures is presented in Section 1.3. 
 

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1.2. 
Study Schema 
 
 
Brensocatib dose and placebo cohorts stratified to include participants who have previously received and will continue to receive cystic fibrosis transmembrane conductance 
regulator (CFTR) modulators as concomitant medication (CFTR modulator stratum), and participants who have either never previously received CFTR modulators or have not 
been administered CFTR modulators within 30 days prior to Screening (visit 1) and will not receive CFTR modulators during the study (non-modulator stratum). 

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1.3. 
Schedule of Assessments and Procedures 
 
Period 
Screening 
Period 
Treatment Period 
Follow-Up Period  
E/D 
Days 
Windows 
-28 to -1 
 
1 
 
2 
 
14 
(±2 days) 
28 (EOT) 
(±2 days) 
29 
(±2 days) 
35 
(±3 days) 
56 (EOS)  
(±2 days) 
 
Visit 
1 
2 
3 
4 
5 
6a 
7a 
8b 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
CFQ-Rc 
 
X 
 
X 
X 
 
X 
 
X 
Inclusion and exclusion 
criteria 
X 
X 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
Medical historyd 
X 
 
 
 
 
 
 
 
 
Substance usage assessmente 
X 
X 
 
 
 
 
 
 
 
Prior and concomitant 
medications 
 
COVID-19 testf 
X 
X 
 
 
 
 
 
 
 
Complete physical 
examinationg 
X 
X 
X 
X 
X 
X 
X 
 
X 
Height, weight, BMIh 
X 
X 
 
 
X 
 
X 
 
X 
Serology testingi 
X 
 
 
 
 
 
 
 
 
Pregnancy test  
(WOCBP only)j 
X 
X 
 
X 
X 
 
X 
 
X 
Serum FSH levelk 
X 
 
 
 
 
 
 
 
 
12-Lead ECGl 
X 
X 
 
X 
X 
 
 
 
X 
Vital signsm 
X 
X 
X 
X 
X 
X 
X 
 
X 

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Period 
Screening 
Period 
Treatment Period 
Follow-Up Period  
E/D 
Days 
Windows 
-28 to -1 
 
1 
 
2 
 
14 
(±2 days) 
28 (EOT) 
(±2 days) 
29 
(±2 days) 
35 
(±3 days) 
56 (EOS)  
(±2 days) 
 
Visit 
1 
2 
3 
4 
5 
6a 
7a 
8b 
 
Laboratory tests (hematology, 
coagulation, urinalysis, 
clinical chemistry)n  
X 
X 
 
 
X 
 
 
 
X 
eGFR 
X 
X 
 
 
X 
 
 
 
X 
Spirometry 
X 
X 
 
 
X 
 
 
 
X 
AEs 
 
X 
SAEs 
 
X 
PK sample collectiono 
 
X 
X 
X 
X 
X 
X 
 
X 
PD sample collection (blood 
and sputum) o 
X 
X 
X 
X 
X 
X 
X 
 
X 
Sputum collection for 
microbiologyo 
 
X 
 
 
X 
 
 
 
X 
Randomization 
 
X 
 
 
 
 
 
 
 
Study drug dispensep 
 
X 
 
X 
 
 
 
 
 
Study drug accountability 
 
 
 
X 
X 
 
 
 
X 
Telephone safety follow-upq 
 
 
 
 
 
 
 
X 
 
a Visit 6 and Visit 7: MUST be scheduled in relation to the actual day of the EOT Visit for PK timing purposes. Visit 6 MUST occur 24 hours after Visit 5, and 
Visit 7 MUST occur 7 days (±24 hours) after Visit 5 for PK sampling purposes (as described in the PK sampling schedule Section 1.3.1 shown below). 
b Visit 8 (EOS Visit): Must occur 4 weeks after the last dose of study drug (4 weeks after Visit 5). 
c CFQ-R should be completed as the first procedure of the visit per FDA guidelines. 
d The diagnosis of bronchiectasis must be confirmed as part of medical history documentation; imaging performed to confirm diagnosis of CF-related lung 
disease should be reported.  
e Substance use is collected on a form separate from the Medical History eCRF. 

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f COVID-19 rapid test should be performed at Screening and on Day 1. Test results should be negative prior to participant randomization.  
g Physical examination: Includes examination of the head (external), eyes, ears, nose, throat, mouth (including gums and teeth), lungs, cardiovascular system, 
abdomen, musculoskeletal system, skin, lymph nodes, and central nervous system. 
h Height, weight, BMI: BMI will be calculated at Screening. 
i Serology testing: HBcAb, HBsAb, HBsAg, HCV, and HIV testing at Screening only. 
j Pregnancy test: Serum pregnancy test at Screening, and urine pregnancy test at Day 1 (Baseline), Day 14, Day 28, Day 35, and at the E/D Visit, if appropriate. 
k Serum FSH level: Female participants are considered postmenopausal if at Screening they have had 12 months of consecutive spontaneous amenorrhea, OR 
< 12 months of consecutive amenorrhea AND a serum FSH level > 40mIU/mL. 
l See the table in Section 1.3.1 for detailed information on ECG, PK, and PD sample collection.  
m Vital Signs: Include body temperature (°C), pulse rate (bpm), respiratory rate (breaths/min), blood pressure (systolic and diastolic [mm Hg]), and oxygen 
 saturation (SpO2). Vital signs will be collected at Screening; predose on Days 1, 2, 14, 28, 29, and 35; and at the E/D Visit, if appropriate. 
n Clinical laboratory tests: Section 8.1.4 contains the description of the clinical laboratory parameters.  
o Sputum for microbiology should be collected at Days 1, 28, and E/D Visit; PD sputum collection should be prioritized if participants are unable to produce a 
sufficient sputum sample. Sputum sample collection will be attempted on all participants per local practice, however, sputum sample collection will not be 
required for participants who cannot provide sputum. 
p Dispense Study Drug: Participants will receive study drug supply on Days 1 and 14. The study drug supply on both days will be sufficient for once daily dosing 
for the entire Treatment Period duration of 28 days (±2 days). Participants will be administered the first dose of study drug on Day 1, at the study center by the 
study center staff. On days of in-clinic visits (except for the Screening Visit), the study center staff will administer the study drug to the participants. On Days 1 
and 28 participants should fast for 8 hours prior to receiving study drug. On days when there is no in-clinic visit, the participant will self-administer the study 
drug with or without food. Instructions on study drug administration are provided in Table 2. 
q Telephone Follow-Up Call: Participants will receive a telephone call from the study center on Day 56 to assess the participant’s well-being.  
Note: All participants are to fast 8 hours prior to attending Day 1 and Day 28 in-clinic visits.  
AE = adverse event, BMI = body mass index, CF = cystic fibrosis, CFQ-R = Cystic Fibrosis Questionnaire-Revised, COVID-19 = coronavirus disease 2019, 
ECG = electrocardiogram, eCRF = electronic case report form, E/D = Early Discontinuation, eGFR = estimated glomerular filtration rate, EOS = End of Study, 
EOT = End of Treatment, FSH = follicle stimulating hormone, HBcAb = hepatitis B core antibody, HBsAb = hepatitis B surface antibody, HBsAg = hepatitis B 
surface antigen, HCV = hepatitis C virus, HIV = human immunodeficiency virus, PD = pharmacodynamic, PK = pharmacokinetic, SAE = serious adverse event, 
WOCBP = women of childbearing potential. 
 
 
 

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1.3.1. 
PK, PD, and ECG Sampling Schedule  
Day 
Timepoint (window) 
PKa  
 
 
PDb (sputum) 
PDb 
(blood) 
ECGc 
Screening 
Period 
Days -28 to -1 
 
 
 
 
X 
X 
X 
Day 1 
Pre-dose 
X 
 
 
X 
X 
X 
 
0.5 h (± 5 min) 
X 
 
 
 
 
 
 
1 h (± 5 min) 
X 
 
 
 
 
 
 
2 h (± 5 min) 
X 
 
 
 
 
X 
 
4 h (± 15 min) 
X 
 
 
 
 
 
 
6 h (± 15 min) 
X 
 
 
 
 
X 
 
8 h (± 15 min) 
X 
 
 
 
 
 
Day 2 
24 h (± 1 h) 
X 
 
 
X 
X 
 
Day 14 
Pre-dose 
X 
 
 
X 
X 
X 
 
2 h (± 5 min) 
X 
 
 
 
 
X 
Day 28 
Pre-dose 
X 
 
 
X 
X 
X 
 
0.5 h (± 5 min) 
X 
 
 
 
 
 
 
1 h (± 5 min) 
X 
 
 
 
 
 
 
2 h (± 5 min) 
X 
 
 
 
 
X 
 
4 h (± 15 min) 
X 
 
 
 
 
 

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Day 
Timepoint (window) 
PKa  
 
 
PDb (sputum) 
PDb 
(blood) 
ECGc 
 
6 h (± 15 min) 
X 
 
 
 
 
X 
 
8 h (± 15 min) 
X 
 
 
 
 
 
Day 29 
24 h (± 1 h) 
X 
 
 
X 
X 
 
Day 35 
168 h (± 24 h) 
X 
 
 
X 
X 
 
E/D 
 
X 
 
 
X 
X 
X 
a PK Sample Collection: Day 1 (predose and at 0.5, 1, 2, 4, 6, 8, and 24 hours postdose [24-hour postdose collection is Day 2 predose collection]), Day 14 
(predose and at 2 hour postdose), Day 28 (predose and at 0.5, 1, 2, 4, 6, 8, 24 (collected on Day 29), and 168 hours postdose (±24 hours; collected on Day 35). 
The collection windows will be up to 30 minutes prior to dosing for the predose sample, ±5 minutes for the 0.5, 1, and 2-hour samples, ±15 minutes for the 4-, 
6-, and 8-hour samples, ± 1 hour for the 24-hour sample, and ± 24 hours for the 168-hour sample. 
 
b PD Sample Collection: Includes collection of 1 sputum sample and 1 blood sample at Screening, and at predose on Days 1, 2, 14, 28, 29, and 35; in addition, at 
E/D Visit, if applicable (the defined pre- and post-dose PK sampling timepoint windows do not apply to PD sample collections). A 6 ml sample of blood should 
be collected at each timepoint. 
c ECG: 12-lead ECG will be performed at Screening, on Day 1 (predose [0 hour], at 2 and 6 hours postdose), on Day 14 (predose and 2 hours postdose), on 
Day 28 (predose, and at 2 and 6 hours postdose), and at the E/D Visit, if applicable, at which only 1 ECG will be performed. The ECG must be conducted 
within a ±10-minute window relative to the PK sampling time. ECG should be collected in triplicates with 10 second recording each.  
ECG = electrocardiogram, E/D = Early Discontinuation, h = hour, min = minute, PK = pharmacokinetic, PD = pharmacodynamic. 
 
 

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2. 
INTRODUCTION 
Cystic fibrosis, an autosomal recessive disorder, is a disease of exocrine gland function that 
involves multiple organ systems, but primarily results in chronic respiratory infections, 
pancreatic enzyme insufficiency, and associated complications. Defects in the CF 
transmembrane conductance regulator gene cause abnormalities of cyclic adenosine 
monophosphate-regulated chloride transport across epithelial cells on mucosal surfaces. 
Defective CFTR results in decreased secretion of chloride and increased reabsorption of sodium 
and water across epithelial cells. The resultant decreased hydration of mucus results in viscous 
mucus, which promotes infection and inflammation. Secretions in the respiratory tract, pancreas, 
gastrointestinal tract, sweat glands, and other exocrine tissues have increased viscosity, making 
them difficult to clear (Ramsey et al., 2019). 
Worldwide incidence of CF varies from 1 per 377 live births (England) to 1 per 90,000 Asian 
live births in Hawaii (Sharma GD, 2020). It is the most common lethal hereditary disease among 
Caucasians in the US (1 case per 2,500 - 3,500 births), with lower incidence among African 
Americans (1 in 17,000 births) and Asian Americans (1 in 31,000 births) (CF News Today, 
2020).  
In 2019, there were 31,199 persons diagnosed with CF in the United States, and of these, the 
majority were Caucasian (93.4%) and male (51.8%). The annual mortality rate (per 100) was 
1.2%, with a median age at death of 32.4 years. However, because of improvements in the 
treatment for CF, the median predicted survival age has continued to increase since 1988: from 
approximately 29 years to 48.4 years (95% CI: 45.9 – 51.5 years) in 2019(CF Foundation 
Registry, 2019). 
Pulmonary outcomes is a key measure of CF health. Pulmonary exacerbations that require 
intravenous antibiotic treatment in the hospital or at home, are associated with morbidity, 
mortality, and decreased quality of life. Uncontrolled PEs often result in prolong hospitalization 
and consequently permanent damage to the lung which manifests as lung function decline (CF 
FoundationRegistry, 2019). The most severe manifestation of CF (and the most frequent cause of 
death or lung transplant) is chronic lung disease with the presence of bilateral disseminated 
bronchiectasis, characterized by chronic lung infection, particularly with Staphylococcus aureus 
and Pseudomonas aeruginosa, and excessive inflammation, declining lung function, and 
eventually respiratory insufficiency.  
Currently available pharmacologic treatment for CF PEs include inhaled antibiotics (tobramycin, 
aztreonam, and colistin), inhaled corticosteroids, leukotriene modifiers, and inhaled beta 
agonists. In spite of improvement in pulmonary function over the years, there has not been a 
marked change in the proportion of individuals with CF who are treated with antibiotics for PEs. 
Approximately 45% of patients 18 years and older were treated with IV antibiotics for 
pulmonary exacerbation from 2005 to 2019 (CF Foundation Registry, 2019). 
2.1. 
Background 
Brensocatib is a reversible, competitive inhibitor of DPP1, with high potency as measured in 
vitro using isolated human DPP1 enzyme and a hematopoietic cell line known to express DPP1. 

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DPP1 activates NSPs, which when released from neutrophils, are proinflammatory and 
destructive to surrounding tissues. Neutrophil elastase is a major product of activated 
neutrophils, and has been identified as a key risk factor in the onset and progression of 
bronchiectasis and lung function decline in patients with CF (Chalmers, 2017; Chalmers et al., 
2017; Sly et al., 2013). Neutrophil elastase has been implicated in the pathogenesis of mucus 
hypersecretion (Fahy and Dickey, 2010; Voynow et al., 2004), airway inflammation (Owen, 
2008; Pham, 2006), and impaired defenses against Pseudomonas aeruginosa infection (Hirche et 
al., 2008; Taggart et al., 2005; Weldon et al., 2009). In addition, NE has been shown to exploit 
basic defects in anion secretion and sodium ion absorption in CF by disabling CFTR chloride 
channels and activating epithelial sodium channels (Le Gars et al., 2013; Mall and Hartl, 2014). 
While NE has gained the most visibility, the other NSPs (ie, CatG and PR3) are expected to 
similarly contribute to the development of bronchiectasis and be associated with increased 
exacerbations. Thus, a pharmaceutical agent that inhibits all NSPs may be superior to one that 
inhibits only NE. 
Brensocatib significantly inhibited the activation of NSPs, resulting in decreased elastolytic 
ability of the cells in vitro. Furthermore, brensocatib produced concentration-dependent 
reductions in both the percentage of neutrophils with membrane-bound PR3 and the overall 
surface expression of PR3 in differentiating human neutrophils in vitro. Studies with naïve and 
lipopolysaccharide-induced pulmonary inflammation models in rats showed that DPP1 inhibition 
with oral brensocatib translates well in vivo, as significant decreases in the activities of NSPs 
were observed. 
Safety pharmacology studies of brensocatib showed no concerning cardiovascular, respiratory, or 
central nervous system effects at a notable safety margin to the systemic exposure in humans at a 
dose level up to 65 mg (single dose). 
In vitro evaluation showed that brensocatib is not a significant inhibitor for CYP isozymes 
(IC50 >30 μM for CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2E1, and 3A4/5) or a significant inducer 
for CYP1A2, 2B6, and 3A4. In addition, it is not a significant inhibitor of transporters, including 
Pgp, BCRP, OATPs, OATs, OCTs, and MATEs (IC50 > 11 μM). Therefore, at a clinically 
relevant concentration range (≤ 1 μM), drug-drug interactions between brensocatib and CYPs 
and transporters modulators are not expected.  
In a Phase 1 study in healthy volunteers (N=81 male participants), who were randomized to 
receive: (a) single doses of placebo or brensocatib (5, 15, 35, 50, or 65 mg), or (b) multiple doses 
of placebo or brensocatib (10, 25, 40 mg QD), daily dosing of brensocatib led to an 
exposure-related reduction in NE activity with a delayed onset of effect consistent with 
neutrophil maturation rates (Palmer et al., 2018). In the presence of potent CYP3A4 and Pgp 
inhibitors (verapamil 240 mg QD or itraconazole 200 mg BID), brensocatib Cmax and AUC were 
altered slightly (14%-32% for AUC and -40%-53% for Cmax). The impact of the CYP3A4 and 
Pgp inhibitors on brensocatib exposure are considered not clinically significant since the altered 
Cmax and AUC were similar to the range of inter-participant variability when brensocatib is dosed 
alone (ca. 20%-50%). Food intake (high-fat meal) showed a minor effect on brensocatib AUC 
(<10% reduction) but moderately delayed the oral absorption (tmax increased by 0-3 hours and 
Cmax decreased by ≤35%). The elimination t1/2 of brensocatib in healthy participants was 
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In the Phase 2b Study INS1007-201, a total of 256 participants with NCFBE who had at least 
2 PEs in the previous year received brensocatib 10 mg QD (N=82), brensocatib 25 mg QD 
(N=87), or placebo (N=87). Brensocatib treatment prolonged the time to the first PE as 
compared with placebo (P = 0.03 and 0.04 for brensocatib 10 mg vs placebo and brensocatib 
25 mg vs placebo, respectively). The adjusted hazard ratio for exacerbation (brensocatib versus 
placebo) was 0.58 (95% CI: 0.35 - 0.95; P = 0.03) in the 10 mg group and 0.62 (95% 
CI: 0.38 - 0.99; P = 0.046) in the 25 mg group. Sputum NE activity was reduced from Baseline 
over the 24-week treatment period for both doses of brensocatib (Chalmers et al., 2020). 
Both the brensocatib 10 and 25 mg doses were well tolerated in Study INS1007-201. TEAEs 
were reported by more participants in the brensocatib treatment groups (75 [92.6%] and 74 
[83.1%] for 10 mg and 25 mg, respectively), than in the placebo group (67 [78.8%]). One 
participant (
-year-old 
with comorbidities; brensocatib 25 mg) had a TEAE of 
respiratory failure (attributed to bronchiectasis progression; not related to study drug) with an 
outcome of death. No clinically meaningful trends or changes in ECGs, clinical laboratory 
values, vital signs, physical examination findings, or postbronchodilator PFTs were observed.  
A large, pivotal, confirmatory, randomized, placebo-controlled study in patients with NCFBE is 
currently ongoing. 
A detailed description of the chemistry, pharmacology, efficacy, and safety of brensocatib is 
provided in the Investigator’s Brochure. 
2.2. 
Study Rationale 
Cystic fibrosis is caused by abnormalities in the CF transmembrane conductance regulator 
protein, causing chronic lung infections (particularly with Pseudomonas aeruginosa) and 
excessive inflammation, and leading to bronchiectasis, declining lung function, and respiratory 
insufficiency. The inflammatory process is dominated by neutrophils that produce NE, as well as 
other destructive NSPs including CatG and PR3, that directly act upon extracellular matrix 
proteins and play a role in the host response to inflammation and infection (Dittrich et al., 2018). 
Brensocatib is a small-molecule inhibitor of the lysosomal cysteine proteinase DPP1 (also known 
as cathepsin C) that is being developed for the treatment of NCFBE and CF. Dipeptidyl 
peptidase 1 activates NSPs, which when released from neutrophils, are proinflammatory and 
generally destructive to surrounding tissues. A reduction in the concentrations of neutrophil 
proteases by means of DPP1 antagonism by brensocatib significantly reduced PEs in patients 
with NCFBE (Study INS1007-201). As bronchiectasis in CF share many common aspects of the 
pathophysiological mechanisms that lead to the development of disease for the population in 
Study INS1007-201, it is reasonable to believe that brensocatib might offer a positive clinical 
response in terms of reduction of exacerbations in patients with CF. Brensocatib administered 
over 4 weeks is expected to produce a decrease in NE, PR3, and CatG concentrations in the 
blood and sputum of participants with CF. The selected dose range, dosing regimen, and 
treatment duration of the current study are based on the biomarker response (blood and/or 
sputum NSP activity) in healthy volunteers, and participants with NCFBE from 
Studies D6190C00001 and INS1007-201 (Willow), respectively. The healthy volunteers 
received brensocatib 10 to 40 mg QD for up to 28 days and had significantly reduced NE activity 
in blood in a dose-dependent manner starting on Day16, reaching maximum PD effect in blood 

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toward the end of the 28-day treatment period. The findings were expanded upon in the Phase 2 
Study INS1007-201 (Willow) by demonstrating mean reductions in sputum samples not only for 
NE activity, but also for the activity of CatG and PR3, for participants on brensocatib compared 
with those on placebo. Activity of NE, PR3, and CatG in sputum returned to baseline levels 
4 weeks after the end of the treatment period (Chalmers et al., 2020). 
In the current study, the selection of the doses (10 to 65 mg) is based on the dose-response 
profile of blood NE activity observed in healthy volunteers (Study D6190C00001) and on the 
sputum NE, PR3, and CatG responses in participants with NCFBE (Study INS1007-201).  
In healthy volunteers, dosing with brensocatib 10 to 40 mg QD inhibited blood NE activity in a 
dose-dependent fashion. In participants with NCFBE, sputum NE, CatG, and PR3 concentrations 
were reduced with daily doses of brensocatib 10 and 25 mg. The appropriate dose for brensocatib 
in patients with CF must take into consideration that the exposure for many drugs is reduced 
when administered to participants with this condition (De Sutter et al., 2020); therefore, a 
potential for reduced exposure to brensocatib may occur, necessitating a higher brensocatib dose 
to achieve a similar response in NSP activity. 
Pathological changes in patients with CF can lead to alterations in drug absorption and 
disposition, including significantly increased renal clearance of orally-administered drugs, 
leading to lower exposure levels (Cmax and AUC). Based on the AUC in healthy volunteers who 
received a single dose of brensocatib 65 mg, the plasma AUC of brensocatib 65 mg QD in 
participants with CF is projected to be ≤10 μg*h/mL, which is approximately a 2-fold margin 
compared to the NOAEL exposure in dogs following 9-month QD dosing at 8 mg/kg (AUC of 
21.6 μg*h/mL). 
Due to differences in nutritional status and fat composition, selecting the optimal dosage in 
patients with CF is a significant challenge. For example, the PK of many antibiotics differ 
between patients with CF and those with other diseases (Bulitta et al., 2007; Zobell et al., 2013). 
Establishing the PK and PD effects of brensocatib in participants with CF is a necessary step in 
the development process. 
The main objective of this study is to determine whether the PK of brensocatib in participants 
with CF differ from those parameters already described in participants with NCFBE. The 
outcomes of this study, including the safety and PK data, and the PK-PD relationships, will 
provide the dose selection rationale for future clinical trials of brensocatib for the CF indication 
in adults. 
2.3. 
Benefit/Risk Assessment 
Detailed information about the known and expected benefits and risks and reasonably-expected 
TEAEs for brensocatib from clinical and nonclinical studies may be found in the Investigator’s 
Brochure. 
2.3.1. 
Benefits  
The current study (Study INS1007-211) is not designed to demonstrate clinical benefit for 
participants. However, the results of this study are necessary for determining the clinical benefit 
to and the correct dosing of brensocatib in patients with CF. This study will be undertaken in 
support of the development of a safe and efficacious treatment for CF. 

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The characteristics of brensocatib that make it a promising candidate for treatment of CF are the 
following, as observed in the Phase 2 study of participants with NCFBE: 
• Both doses of brensocatib (10 and 25 mg QD for 24 weeks) in Study INS1007-201 
provided statistically significant and clinically relevant prolongation of time to PE 
compared with placebo 
• In Study INS1007-201, brensocatib 10 mg QD for 24 weeks provided a statistically 
significant and clinically relevant treatment effect on the annualized rate of PEs 
compared with placebo, and brensocatib 25 mg QD for 24 weeks showed a 
numerically lower rate of PEs than with placebo  
• Brensocatib reduced sputum NE concentrations in a dose-dependent manner, 
supporting the proposed mechanism of action  
• Achievement of sputum NE concentrations below the limit of quantification 
postbaseline provided a clinically relevant and statistically significant effect on time 
to PE 
2.3.2. 
Risks 
Key risks of treatment with brensocatib are primarily those effects related to DPP1 inhibition, 
similar to those effects experienced by patients with PLS, a rare genetic condition in which DPP1 
activity is severely reduced (Guarino et al., 2017); (Sorensen et al., 2014): 
• Palmoplantar keratosis, characterized by redness and thickening of the soles and 
palms 
• Periodontitis (can be severe enough to cause tooth loss by the second or third decade 
of life) (Toomes et al., 1999) 
• Increased incidence of infections (including severe infections) 
•  As in the Studies INS1007-101 (healthy volunteers; single and multiple doses [10, 
25, 40 mg]) and INS1007-201 (patients with NCFBE; brensocatib 10 and 25 mg QD 
vs placebo QD for 24 weeks), hyperkeratosis, gingivitis/periodontitis, and infections 
will be monitored as AESIs. 
2.3.3. 
Overall Benefit: Risk Conclusions 
Although there is no clinical experience with brensocatib in patients with CF, the information 
available to date from the clinical program in patients with NCFBE is supportive of a positive 
benefit-risk ratio in CF patients as well.  
In the Phase 2 study, treatment with brensocatib for 24 weeks significantly prolonged time to 
first exacerbation (both the 10 mg and 25 mg doses) and lowered annualized rates of 
exacerbation compared with placebo (10 mg dose). Results were consistent among subgroups 
based on age, baseline NE concentrations, prior exacerbation history, bronchiectasis severity 
index, and lung function. The reduction in sputum NE concentration appeared to be greater with 
the 25 mg dose. 

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The overall safety profile was similar across treatment groups in both the Phase 1 
(Study INS1007-101) and Phase 2 (Study INS1007-201) trials. Although treatment-emergent 
skin and dental-related AESIs were numerically higher with active treatment, the events resolved 
or were recovering at the end of study. The skin events reported had no resemblance to lesions in 
PLS and did not lead to treatment discontinuation. Infections were similar across treatment 
groups, and fewer participants in the active treatment groups reported serious adverse 
events (SAEs) of infective exacerbation of bronchiectasis. No new safety signals were identified. 
Detailed information is provided in the Investigator’s Brochure. 
Based on the collective information from the healthy volunteers and patients with NCFBE, and 
given the common aspects of the pathophysiology between NCFBE and CFBE, it is reasonable 
to hypothesize that a positive treatment effect of brensocatib in patients with CF could be 
expected. In conclusion, brensocatib offers a positive benefit-risk ratio to support its dosing in 
patients with CF.

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Objectives 
Endpoints 
To evaluate the PK/PD relationship between 
AUC/dose and biomarker activity (blood 
and/or sputum) 
NE, CatG, and PR3 concentrations between 
Day 14 and Day 28 in blood and sputum vs. 
brensocatib exposure at steady state 
 
To evaluate the PK/PD relationship between 
systemic exposure and safety (eg, AESIs of 
hyperkeratosis, periodontitis/gingivitis, and 
infections) 
 
AESIs during the 28-day treatment period 
and their relationship to brensocatib 
exposure at steady state 
To evaluate the PK/PD relationship between 
systemic exposure and clinical efficacy (ie, 
ppFEV1 and CFQ-R) 
ppFEV1 and CFQ-R during the 28-day 
treatment period and their relationships with 
brensocatib exposure at steady state 
 
To evaluate the effect of brensocatib on 
sputum microbiology 
Change from Baseline to Day 28 in number 
of colony forming units for microbial 
species. 
 
a Frequency of TEAEs includes clinically significant vital signs and laboratory abnormalities. 
AESI = adverse events of special interest, AUC = area under the concentration-time curve, AUClast = AUC from time 0 to the last 
timepoint with measurable concentration, AUC0-24 = AUC from time 0 to 24 h postdose, CatG = cathepsin G, CFQ-R = Cystic 
Fibrosis Questionnaire-Revised, Cmax = maximum plasma concentration, FEF(25-75%) = forced expiratory flow between 25% and 
75% of forced vital capacity, FEV1 = forced expiratory volume in 1 second, FVC = forced vital capacity, NE = neutrophil 
elastase, PD = pharmacodynamic, PK = pharmacokinetic(s), ppFEV1 = percent predicted forced expiratory volume in 1 second, 
PR3 = proteinase 3, t½ = elimination half-life, tmax = time to maximum plasma concentration 

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4. 
STUDY DESIGN 
4.1. 
Overall Design 
This is a Phase 2a, single-blind, randomized, placebo-controlled, parallel-group, multiple-dose 
study to assess the PK, PD, and safety of brensocatib 10, 25, and 40 mg QD in participants with 
CF. Following review of safety and PK data by the SRC and provided that the SRC deems it 
appropriate to administer the next higher dose, an additional cohort of participants will receive 
brensocatib 65 mg QD on the same schedule as the previous cohorts. A tablet formulation of 
brensocatib 65 mg is not yet available; therefore, participants randomly assigned to the 65 mg 
dose cohort will receive the following:  
• 1 tablet of brensocatib 25 mg QD plus 1 tablet of brensocatib 40 mg QD × 28 days 
OR 
• 2 tablets of matching placebo QD × 28 days 
Section 6.3 describes the procedures for blinding the study drug. 
Overall, the study will enroll approximately 25 to 34 participants. The first three brensocatib 
dose cohorts (10 mg, 25 mg, and 40 mg QD) will enroll approximately 7 participants each, and 
the placebo cohort will enroll approximately 4 participants. 
For many patients with CF, CFTR modulators are the cornerstone of their treatment (van der 
Meer et al., 2021). The proportion of patients prescribed a CFTR modulator has expanded over 
time, with approximately only 14% of the eligible population not prescribed a CFTR modulator 
(CF Foundation Registry, 2020). For the active treatment dose cohorts, there will be 2 strata: 
approximately 5 participants who have previously received and will continue to receive CFTR 
modulators as concomitant medication (CFTR modulator stratum), and approximately 
2 participants who have either never previously received CFTR modulators or have not been 
administered CFTR modulators within 30 days prior to Screening (visit 1) and will not receive 
CFTR modulators during the study (non-modulator stratum). For the placebo cohort, 
approximately 3 participants will be randomized into the CFTR modulator stratum and 
1 participant in the non-modulator stratum. 
As described in Table 1, each cohort will enroll participants in a 5:1 ratio (active : placebo) for 
the CFTR modulator stratum. For the non-modulator stratum, approximately 6 participants will 
be randomized to receive active treatment (10 mg, 25 mg, and 40 mg brensocatib) and 
approximately 1 participant to placebo.  
If there are no safety issues observed in the first 3 dose cohorts, a 65 mg dose cohort will be 
similarly randomized: 7 participants (5 participants CFTR modulator and 2 participants 
non-modulator stratum) in active treatment and 2 participants in placebo (1 participant each in 
the CFTR modulator and non-modulator strata), increasing the sample size from approximately 
25 to 34 participants. 

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An SRC (Section 4.1.5) will be set up to review safety and PK data as part of the 
decision-making process to determine whether to implement the brensocatib 65 mg dose. 
4.1.1. 
Screening Period 
The Screening Period will be up to 28 days. Required screening assessments are shown in the 
SoA, Section 1.3. Participants who fail 1 or more screening assessments may be rescreened at the 
Investigator’s discretion. Section 5.4 contains additional information regarding participants who 
fail screening and/or are rescreened. 
4.1.2. 
Treatment Period 
The Treatment Period is a 28-day period comprising 4 in-clinic visits on Days 1, 2, 14, and 28. 
Participants must enter the study at the start of either their on-treatment or off-treatment cycled 
antibiotic regimen. All Treatment Period assessments and procedures are presented in the SoA, 
Section 1.3.  
4.1.2.1. 
Day 1 (Baseline) 
Participants will return to the study center after an 8-hour fast on Day 1 (Baseline) and undergo 
assessments (inclusion/exclusion criteria, concomitant medications, AEs), and procedures 
(physical examination, 12-lead ECG, vital signs, clinical laboratory tests, spirometry). Additional 
procedures and assessments are listed in the SoA, Section 1.3. After assessments and procedures 
are completed, eligible participants will be randomized to receive brensocatib 10, 25, or 40 mg or 
placebo QD, orally for 4 weeks. The study center staff will administer the study drug to 
participants for days of in-clinic visits. On Days 1 and 28, the study center staff will administer 
the study drug to the participant after 8 hours of fasting on Days 1 and 28. Participants will 
receive a 28-day supply of blinded study drug on Days 1 and 14. On days when there is no in-
clinic visit, the participant will self-administer the study drug with or without food at the same 
time of day each day.  
4.1.2.2. 
Day 2, Day 14, and Day 28 
Participants will return to the study center on Days 2, 14, and 28 (End of Treatment [EOT]), and 
report all concomitant medications taken and any AEs that have occurred since the last study 
visit. All Treatment Period assessments and procedures are listed in the SoA, Section 1.3. 
Participants will return to the study center after an 8-hour fast on Days 1 and 28. Participants will 
bring study drug bottles and any unused medication for study drug accountability to the Day 14 
Visit and return the study drug bottles and any unused medication for study drug accountability 
on the Day 28 (EOT) Visit.  
4.1.3. 
Follow-Up Period 
The Follow-Up Period will extend from Day 29 to Day 56 (EOS) and include visits to the study 
center on Day 29 and Day 35 for blood sampling for PK analysis, and for blood and sputum 
sampling for PD analysis (Section 1.3). On Day 56 (EOS) a telephone call will be placed from 
the study center to the participant to check on well-being and to assess the status of any new 
and/or ongoing AEs. 

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4.1.4. 
Decision to Dose Brensocatib 65 mg 
A decision to dose a fourth cohort with brensocatib 65 mg or placebo will be made after the first 
3 cohorts have completed the study. Section 4.1.5 describes information on the SRC and its role 
in determination of the fourth dosing cohort. 
If a cohort dosed with brensocatib 65 mg is approved, participants in the cohort will be supplied 
with bottles of study drug sufficient to dose with 2 tablets QD for 28 days on Days 1 and 14, 
following the same procedures as the previous cohorts.  
As there is currently no 65 mg tablet of brensocatib, each participant in the cohort will take one 
25 mg tablet and one 40 mg tablet, or 2 placebo tablets at the same time each day for 28 days, to 
maintain the blind. Detailed instructions on handling the investigational product will be 
described in the pharmacy manual and medication card. 
4.1.5. 
Safety Review Committee 
Safety monitoring of the study will be conducted by an SRC. After the first 3 cohorts 
(brensocatib 10, 25, and 40 mg QD) have completed the study, the SRC will review available 
data (PK and safety data [vital signs, clinical laboratory test values, ECGs, and AEs]) in an 
unblinded manner from all cohorts to determine if brensocatib has shown an acceptable safety 
and PK profile and whether the brensocatib dose should be escalated to 65 mg QD as planned. If 
significant safety issues arise in between scheduled meetings, ad hoc meetings will be scheduled 
to review those data. 
The decision on whether the MTD has been reached will be based on the DLT. The MTD is 
defined in this study as the highest single dose tested without incurring DLT. The signs and 
symptoms to consider for DLT include any events that in the opinion of the SRC are relevant to 
brensocatib exposure, including but not limited to hyperkeratosis, severe infection, and 
periodontal disease. The PK profile will also be considered and compared with those of other 
populations (healthy volunteers and patients with NCFBE) to assess whether similar levels of 
exposure have been achieved with the evaluated doses.  
The structure of the SRC is described in Section 10.1.8.  
4.2. 
Scientific Rationale for Study Design 
Study INS1007-211 is a randomized single-blind, placebo-controlled study. Placebo control 
eliminates bias and ensures that any differences among treatment groups are due to the active 
drug. The use of multiple doses of study drug to assess the PK and PD of brensocatib in a 
specific patient population (in this case, participants with CF), is standard practice in order to 
determine the dose and dosing regimen that achieves target drug exposures in all relevant 
populations. 
Safety parameters are standard and meet the ICH requirements for safety reporting. As a single-
blind study, participants are blinded to their assigned study drug and dose, as are the study center 
staff and the Investigator. Select Sponsor personnel are not blinded, including the Independent 
Clinical Pharmacologist and SRC members. Blinding is maintained by means of an IWRS 
system for assigning treatment. 

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Efficacy measures include spirometry, which is a validated method for assessing respiratory 
function, and the CFQ-R, a validated instrument for assessing quality of life for patients with CF. 
4.3. 
Justification for Dose 
Brensocatib has been studied using solution and tablet formulations in healthy volunteers, with 
dosing strengths ranging from 5 to 65 mg, and repeated administrations of 10 mg, 25 mg, and 
40 mg across the formulations that support similar conclusions of dose proportionality. 
A Phase 2 Study (INS1007-201) that randomized 256 participants with NCFBE demonstrated the 
efficacy of brensocatib in reducing PEs when administered at 10 mg and 25 mg in comparison to 
placebo. Furthermore, both doses demonstrated an acceptable safety profile as most TEAEs were 
mild to moderate in intensity across groups; those reported in ≥10% of brensocatib-treated 
participants were cough, headache, increased sputum, and dyspnea, with some potential 
indication of dose dependency for events that may reflect DPP1 inhibition. Modeling and 
simulations using data from the Phase 2 study support that a reduction of sputum NE below 
quantification levels is associated with a reduction of exacerbations, and that such reduction is 
dose dependent.  
In patients with CF, the airway inflammation is dominated by neutrophils that produce reactive 
oxygen species, neutrophil extracellular traps, proteases such as NE, PR3, and CatG, and 
proinflammatory mediators. Neutrophils are the source of the massive amounts of free elastase in 
the CF airway (Nichols and Chmiel, 2015). Elastase possesses several deleterious characteristics 
that account for much of the lung damage seen in CF, and the amount of free elastase in the 
airway highly correlates with lung function (FEV1) (Sagel et al., 2012). 
Two main factors were taken into consideration regarding dosing for the current study: 
• Levels of NE in patients with CF have been described to be higher than in patients 
with NCFBE (Oriano et al., 2019). 
• Patients with CF are often reported to have higher clearances and larger volumes of 
distribution for a given medication per kilogram of total body weight than healthy 
volunteers (Bulitta et al., 2011), and many patients with CF report some level of 
chronic malabsorption.  
Based on the findings listed above, it seems reasonable to assess doses higher than those 
included in the Phase 2 study previously described. Accordingly, the first 3 cohorts (brensocatib 
10, 25, and 40 mg) will be dosed concurrently, and an SRC will review safety and PK data from 
these cohorts. After review, the SRC will decide whether exploring brensocatib 65 mg is 
appropriate.  
4.4. 
End of Treatment Definition 
A participant is considered to have completed treatment if they have completed Day 28 of the 
study, including the scheduled procedures shown in the SoA (Section 1.3). 

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4.5. 
End of Study Definition 
The end of the study is defined as the date of the last assessment of the last participant in the 
study (Section 1.3). A participant reaches EOS if they have completed Day 56 of the study, 
including the scheduled procedures shown in the SoA (Section 1.3). 

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5. 
STUDY POPULATION 
The study is expected to enroll approximately 25 to 34 participants at 1 or more centers in the 
US. 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted. 
5.1. 
Inclusion Criteria 
Participants are eligible to be included in the study only if all of the following criteria apply: 
Age 
1. Participants must be ≥18 years of age at the time of signing the informed consent. 
Type of Participant and Disease Characteristics 
2. Male or female participants with a confirmed diagnosis of CF related lung disease 
a.  ppFEV1 between 40% to 90% (inclusive) at Screening Visit and at 
Baseline 
b. Stable CF treatment for at least 30 days before Screening and willing to 
remain on a stable regimen throughout the treatment period  
Weight 
3. Has a body mass index ≥18 kg/m2  
Sex and Contraceptive/Barrier Requirements 
4. Male and female participants must use contraceptives that are consistent with local 
regulations regarding the methods of contraception for those participating in 
clinical studies. 
a. Male participants: 
Male participants, who are not sterile, with female partners of childbearing 
potential must be using effective contraception from Day 1 to at least 90 
days after the last dose. Such methods include true abstinence (refraining 
from heterosexual intercourse during the study), combined (estrogen and 
progestogen containing) or progestogen-only hormonal contraception 
associated with inhibition of ovulation, intrauterine devices, intrauterine 
hormone-releasing systems. 
 
b. Female participants: 
Women must be postmenopausal (defined as no menses for 12 months 
without an alternative medical cause), surgically sterile, or using highly 
effective contraception methods (ie, methods that alone or in combination 
achieve <1% unintended pregnancy rates per year when used consistently 

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and correctly) from Day 1 to at least 90 days after the last dose. Such 
methods include true abstinence (refraining from heterosexual intercourse 
during the study), combined (estrogen and progestogen containing) or 
progestogen-only hormonal contraception associated with inhibition of 
ovulation and supplemented with a double barrier (preferably male 
condom), intrauterine devices, intrauterine hormone-releasing systems, or 
vasectomized partner. For WOCBP ≤45 years, an additional confirmatory 
testing of FSH level with a threshold of >40 mIU/mL should be performed 
to be considered infertile.  
Note: Abstinence is only considered to be a highly effective method of 
contraception when this is the preferred and usual lifestyle of a participant. 
Periodic abstinence (calendar, symptothermal, postovulation methods), 
withdrawal (coitus interruptus), spermicides only, and lactational 
amenorrhoea method are not acceptable methods of contraception. 
5. Female participants of childbearing potential must have a negative serum 
pregnancy test at Screening. 
6. Male participants with pregnant or nonpregnant WOCBP partners must use a 
condom. 
Informed Consent 
7. Participant is capable of giving signed informed consent as described in 
Section 10.1.5, which includes compliance with the requirements and restrictions 
listed in the ICF and in this protocol. 
8. Able to understand and comply with protocol requirements, restrictions, and 
instructions and likely to complete the study as planned, as judged by the 
Investigator. 
 
5.2. 
Exclusion Criteria  
Participants are excluded from the study if any of the following criteria apply: 
Medical Conditions 
1. Severe or unstable CF as per Investigator’s judgement. 
2. Oxygen saturation (SpO2) on room air ≤92% at the Screening Visit and at Baseline 
3. Currently being treated for allergic bronchopulmonary aspergillosis or 
nontuberculous mycobacteria or TB. 
4. Active and current infection by SARS-CoV-2. 

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5. Screening test results (hematology, clinical chemistry, coagulation, and/or 
urinalysis) with clinically significant abnormalities that would interfere with the 
study assessments, as judged by the Investigator, including the following: 
• Hemoglobin <10 g/dL at Screening. 
• An ANC <1,000/mm3 at Screening. 
• Clinically significant hepatobiliary disease defined as alanine 
aminotransferase (ALT) and/or aspartate aminotransferase (AST) values 
>3 × upper limit of normal (ULN) and total bilirubin >2 × ULN, excluding 
confirmed Gilbert’s Syndrome 
• Abnormal renal function test result at Screening, defined as eGFR 
<30 mL/min (by the Chronic Kidney Disease – Epidemiology 
Collaboration equation formula) (Levey et al., 2009) for participants 
18 years and older. 
6. History of malignancy in the past 5 years, except completely treated in situ 
carcinoma of the cervix and completely treated non-metastatic squamous or basal 
cell carcinoma of the skin. 
7. History of any illness or condition that, in the opinion of the Investigator, might 
confound the results of the study or pose an additional risk in administering study 
drug to the participant. 
8. Established diagnosis of hepatitis B viral infection or positive for HBsAg at 
Screening: 
− Participants who have gained immunity for hepatitis B virus infection after 
vaccination (participants who are HBsAg-negative, HBsAb-positive, and 
HBcAb-negative) are eligible for the study. 
− Participants with positive HBcAb are eligible for the study only if hepatitis B 
virus DNA level is undetectable. 
9. Established diagnosis of HCV infection at Screening. Participants positive for 
hepatitis C antibody are eligible only if HCV RNA is negative. 
10. History of HIV infection or positive HIV serology at Screening. 
11. Acute upper or lower respiratory tract infection, pulmonary exacerbation, or 
changes in therapy (including IV and oral antibiotics) for pulmonary disease within 
4 weeks prior to Day 1 (administration of the first dose of study drug). Participants 
meeting this criterion could be rescreened 4 weeks after resolution of symptoms. 
12. History of prolonged QT/QTc interval with QTcF >480 msec at Screening. 
13. History of solid organ or hematological transplantation. 

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14. Any clinically significant abnormal laboratory values at Screening or diseases or 
disorders (eg, survivors of severe COVID-19 disease including ARDS, 
cardiovascular, pulmonary, gastrointestinal, liver, kidney, neurological, 
musculoskeletal, endocrine, metabolic, psychiatric, physical impairment, or a lung 
transplantation) that, in the opinion of the Investigator, may put the participant at 
risk by participating in the study, or interfere with the participant's treatment, 
assessment, or influence the results of the study, or have compliance issues with 
the study or have a planned or anticipated major surgical procedure during the 
study. 
15. Unstable disease due to colonization with Burkholderia cenocepacia, Burkholderia 
dolosa, and Mycobacterium abscessus as judged by the Investigator. 
16. Any “non-CF-related” acute illness within 2 weeks prior to Day 1 (first dose of 
study drug). “Illness” is defined as an acute (serious or nonserious) condition 
(eg, gastroenteritis). 
17. Have diagnosed periodontal disease and are either: 
− Currently treated by a dentist for this condition or 
− Expected to have periodontal disease-related procedures within the study 
period. 
18. Received any live attenuated vaccine within 4 weeks prior Screening. If a live 
vaccine has been administered, the participant should wait 4 weeks prior to 
rescreening. During the study, participants may not receive any live attenuated 
vaccine. 
Prior/Concurrent Clinical Study Experience 
19. Ongoing participation in another therapeutic clinical study or prior participation in 
an investigational drug study within 90 days prior to Screening. A washout period 
of ≥5 terminal half-lives of the previous investigational study drug or 90 days, 
whichever is longer, must elapse prior to Screening. 
20. Known history of hypersensitivity to brensocatib or any of its excipients 
21. Use of any immunomodulatory agents within 4 weeks before the Screening Visit is 
prohibited during the study through Visit 8 (EOS) (including, but not limited to: 
bortezomib, ixazomib, thalidomide, cyclophosphamide, mycophenolate, Janus 
kinase inhibitors, IFN-γ, and azathioprine). 
22. Continuous use of high-dose NSAIDs is prohibited during the study through Visit 8 
(EOS) (Section 10.6.1). 
Alcohol and Tobacco 
23. History of alcohol, medication, or illicit drug abuse. 

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24. Current smoker, as defined by Centers for Disease Control and Prevention: An 
adult who has smoked 100 cigarettes in his or her lifetime and who currently 
smokes cigarettes. 
 
5.3. 
Lifestyle Considerations 
Not applicable. 
5.4. 
Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently randomized to receive study drug. A minimal set of screen failure information 
is required to ensure transparent reporting of screen failure participants to meet the Consolidated 
Standards of Reporting Trials publishing requirements and to respond to queries from regulatory 
authorities. Minimal information includes demography, screen failure details, eligibility criteria, 
and any SAE. 
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened after consultation with the study Medical Monitor. Participants who meet all 
inclusion criteria but fail screening due to active PE or ongoing standard periodontal care can be 
rescreened up to 2 times with the Sponsor’s Medical Director approval. If a participant is 
approved for rescreening, the Medical Director will determine whether some or all of the 
screening assessments must be repeated.  
NOTE: Rescreened participants should be assigned a new participant number (“subject ID”) by 
the IWRS system for every screening/rescreening event. 
5.5. 
Criteria for Temporarily Delaying Administration of Investigational 
Product 
Not applicable. 

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6. 
INVESTIGATIONAL PRODUCT AND CONCOMMITANT 
THERAPY 
Investigational product is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according to the 
study protocol. In this protocol, the terms “investigational product” and “study drug” are 
interchangeable. 
Brensocatib film-coated tablets are round, biconvex, brown, film-coated tablets containing the 
equivalent of 10 mg, 25 mg, and 40 mg of brensocatib (INS1007) drug substance and to be 
administered orally QD. Each film-coated tablet contains active ingredient of brensocatib drug 
substance and compendial ingredients: microcrystalline cellulose, dibasic calcium phosphate 
dihydrate, sodium starch glycolate, silicon dioxide, and glyceryl behenate. 
Participants will be assigned to receive brensocatib 10, 25, or 40 mg QD or placebo QD for 
28 days. They will be randomly assigned to a dosing cohort with 10 participants receiving active 
drug and 2 participants receiving placebo (12 participants per cohort). Insmed will provide sites 
with the investigational products as described in Table 2. 
Participants will receive the same number of tablets each day to maintain the blind. 
If the 65 mg is to be assessed, participants in this cohort will receive 65 mg QD (25 mg + 40 mg 
tablets) or matching placebo tablets on the same schedule as the previous cohorts. 
6.1. 
Investigational Product Administration 
Participants will be instructed to take 1 tablet of the study drug once a day, with water and with 
or without food, at approximately the same time of day each day in the morning. On the days of 
in-clinic visits the study drug will be administered by the study center staff. On Day 1 and Day 
28 visits, participants will visit the study center and receive study drug after an 8-hour overnight 
fast. Except for Days 1 and 28, the study drug can be administered with or without food. 
Details about the study drug are presented in Table 2. 

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Table 2: 
Investigational Product for Study INS1007-211 
Arm Name: 
Placebo 
Brensocatib 
Unit Dose: 
 
10 mg 
25 mg 
40 mg 
65 mg 
Type: 
Placebo 
Drug 
Drug 
Drug 
Drug 
Formulation: 
Tablet 
Tablet 
Tablet 
Tablet 
N/Aa 
Route: 
Oral 
Oral 
Oral 
Oral 
Oral 
Use: 
Experimental 
Experimental 
Experimental 
Experimental 
Experimental 
Manufacturer: 
Insmed 
Insmed 
Insmed 
Insmed 
Insmed 
Packaging and 
Labeling: 
Study drug 
will be 
provided in 
HDPE bottles 
Study drug 
will be 
provided in 
HDPE bottles 
Study drug 
will be 
provided in 
HDPE bottles 
Study drug 
will be 
provided in 
HDPE bottles 
Study drug 
will be 
provided in 
HDPE bottles 
Administered 
As: 
One placebo 
tabletb 
One 10-mg 
brensocatib 
tablet 
One 25-mg 
brensocatib 
tablet 
One 40-mg 
brensocatib 
tablet 
One 25-mg 
brensocatib 
tablet 
AND 
one 40-mg 
brensocatib 
tablet 
a Currently no 65 mg tablet exists. Participants who are randomized to brensocatib 65 mg will receive 2 bottles of 
study drug with different color labels on the bottles (1 bottle with brensocatib 25 mg tablets, 1 bottle with 40 mg 
tablets) and will take 1 tablet from each bottle on each dosing day. 
b In the 65 mg dose cohort, participants randomly assigned to placebo will receive 2 bottles of study drug, both 
containing placebo tablets. To preserve the blind, participants will take 1 tablet from each bottle on each dosing 
day. 
 
HDPE = high-density polyethylene, N/A = not applicable. 
6.2. 
Preparation/Handling/Storage/Accountability 
The Investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study drug received and any discrepancies are reported and 
resolved before use of the study drug. Study drug will be stored at temperatures as indicated on 
the label. 
Only participants enrolled in the study may receive study drug and only authorized site staff may 
supply or administer study drug. All study drug must be stored in a secure, environmentally 
controlled, and monitored (manual or automated) area in accordance with the labeled storage 
conditions with access limited to the Investigator and authorized site staff. 
The Investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study drug accountability, reconciliation, and record maintenance (ie, receipt, 
reconciliation, and final disposition records). 
Further guidance and information for the final disposition of unused study drugs are provided in 
the Study Pharmacy Manual. 

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6.3. 
Measures to Minimize Bias: Randomization and Blinding 
After meeting all inclusion criteria and none of the exclusion criteria, participants in each stratum 
(CFTR modulator and non-modulator) will be randomized by means of an IWRS in a 1:1:1 ratio 
to 1 of the first 3 dose cohorts (brensocatib 10, 25, or 40 mg); each cohort will enroll participants 
in a 5:1 ratio (active : placebo) for the CFTR modulator stratum. For the non-modulator stratum, 
approximately 6 participants will be randomized to active treatment in the first 3 dose cohorts 
and 1 participant will be assigned placebo. If there are no safety issues in these cohorts, a 65 mg 
dose cohort will be similarly randomized: 7 participants (5 participants CFTR modulator and 
2 participants non-modulator stratum) in active treatment and 2 participants in 
placebo (1 participant each in the CFTR modulator and non-modulator strata), raising the total 
sample size from approximately 25 to 34 participants.  
This is a single-blind study: participants are blinded to the study drug to which they are randomly 
assigned, as are the study center staff and the Investigator. Select Sponsor personnel comprising 
the SRC members and the Independent Clinical Pharmacologist are not blinded. The site will 
contact the IWRS prior to the start of study drug administration for each participant. The site will 
record the assigned study drug label number on the applicable electronic case report 
form (eCRF), if required. 
Study personnel and participants are strongly discouraged from discussing any aspect of study 
treatment, with the exception of safety issues, to maintain treatment blinding and study integrity. 
The IWRS will be programmed with blind-breaking instructions. In case of an emergency, the 
Investigator has the sole responsibility for determining whether unblinding of a participant’s 
study drug assignment is warranted. Participant safety must always be the first consideration in 
making such a determination. If the Investigator decides that unblinding is warranted, the 
Investigator should make every effort to contact the Sponsor prior to unblinding a participant’s 
study drug assignment unless this could delay emergency treatment of the participant. If a 
participant’s study drug assignment is unblinded, the Sponsor must be notified within 24 hours 
after breaking the blind. The date and reason that the blind was broken must be recorded in the 
source documentation, as applicable. 
6.4. 
Study Drug Compliance 
When participants are dosed at the site, they will receive study drug directly from the 
Investigator or designee, under medical supervision. The date and time of each dose 
administered in the clinic will be recorded in the source documents. The dose of study drug and 
study participant identification will be confirmed at the time of dosing by a member of the study 
site staff other than the person administering the study drug. Study site staff will examine each 
participant’s mouth to ensure that the study drug was ingested. 
When participants self-administer study drug, compliance will be assessed at each visit. Drug 
accountability will be assessed by counting returned tablets during the site visits on Days 14 and 
28 and documenting in the source documents and relevant forms. Deviation(s) from the 
prescribed dosage regimen should be recorded. 

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A record of the quantity of brensocatib tablets dispensed to and administered by each participant 
must be maintained and reconciled with study drug and compliance records. Start and stop dates, 
including dates for delays will also be recorded.   
6.5. 
Dose Modification 
Not applicable. 
6.6. 
Continued Access to Investigational Product After the End of the 
Study 
Not applicable. 
6.7. 
Overdose 
An overdose is defined as a dose greater than the dose level(s) evaluated in this study. There is 
no known antidote to the study treatment. 
An overdose itself is not an AE. However, any clinical signs and symptoms associated with the 
overdose should be reported via the SAE form within 24 hours of awareness, even if no 
seriousness criteria for the events are met. 
The Investigator should also: 
• Contact the Medical Monitor in case of symptomatic overdose within 24 hours 
• In consultation with the Medical Monitor, determine whether the study drug should 
be interrupted or discontinued  
• Closely monitor the participant for any AE/SAE and laboratory abnormalities and 
follow them up until they resolve 
• Fully document the overdose (eg, intentional or accidental, the dose, duration of the 
overdose) and associated signs and symptoms in the participant’s source documents 
and the appropriate case report form (CRF) pages. 
6.8. 
Concomitant Therapy 
Any medications the participant takes other than the study drug from Day 1 (Baseline) to Day 56 
(EOS) are considered concomitant medications and will be collected and documented in the 
study eCRF.   
Prior medications are those medications taken before the first dose of study drug. Concomitant 
medications are those medications taken after the first dose of study drug. A medication that 
starts prior to first dose but continues after the first dose of study drug is classified both in prior 
and concomitant medications. Prior procedures are procedures performed before the first dose of 
study drug. Any procedures performed from Day 1 to Day 56 (EOS) are considered concomitant 
procedures and will be collected and documented in the study eCRF. 
The Medical Monitor should be contacted if there are any questions regarding concomitant or 
prior therapy. 

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Participants must begin the study at the start of either their on-treatment or off-treatment cycled 
antibiotic regimen.  
As stated in the Section 2, brensocatib interactions with substrates or modulators of CYP3A4 and 
Pgp are unlikely at the dose levels of 10 mg to 65 mg. 
6.8.1. 
Rescue Medicine 
Not applicable. 
6.8.2. 
Dose Interruption 
The Investigator may interrupt dosing for safety reasons. 
6.8.3. 
Prohibited Medications 
Prohibited medications are as follows: 
• Use of any immunomodulatory agents within 4 weeks before the Screening Visit is 
prohibited during the study through Visit 8 (EOS) (including, but not limited to: 
bortezomib, ixazomib, thalidomide, cyclophosphamide, mycophenolate, Janus kinase 
inhibitors, IFN-γ, and azathioprine)  
• Continuous use of high dose NSAIDs is prohibited during the study through Visit 8 
(EOS) (Section 10.5.1, Comparable NSAID Dose Levels)  
• Long-term use of systemic steroids (>4 weeks, regardless of dose) for any chronic 
condition 
• Live attenuated vaccines are prohibited during the study from 4 weeks prior to 
Screening until 4 weeks after the last dose of the study drug 
• Use of investigational drugs within 90 days or ≥5 terminal half-lives of the previous 
investigational study drug (whichever is longer) of the Screening Visit 
The following procedures are prohibited during study participation:  
• Major elective surgical procedures 
• Elective periodontal procedures  
Participants who have already scheduled a major surgical procedure or a prescheduled 
periodontal procedure are not eligible to participate in the study. 

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7. 
DISCONTINUATION OF STUDY DRUG AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL 
7.1. 
Discontinuation of Study Drug 
Participants who discontinue the study drug for any reason may not continue in the study unless 
discontinuation was due to an AE. Participants who discontinue the study will be asked to attend 
an Early Discontinuation Visit and undergo the scheduled assessments (SoA, Section 1.3). 
7.1.1. 
QTc Stopping Criteria 
If a clinically significant finding is identified (including, but not limited to QTcF >480 msec) 
after enrollment, the Investigator or qualified designee will determine whether the participant can 
continue in the study and whether any change in participant management is needed. This review 
of the ECG printed at the time of collection must be documented. Any new clinically relevant 
finding should be reported as an AE. 
7.1.2. 
Pregnancy 
Refer to Section 8.2.5. 
7.1.3. 
Participant Discontinuation/Withdrawal From the Study 
A participant may decide to withdraw from the study at any time, for any reason, without 
prejudice to subsequent care or treatment by the Investigator. When this occurs, the participant 
should complete all the procedures for the Early Discontinuation Visit. Participants who 
discontinue the treatment due to AEs should remain under observation until the resolution or 
stabilization of the AEs. A participant may be discontinued from the study drug treatment before 
completion for any of the following reasons: 
1. Participant death 
2. Participant experiences an AE(s)/SAE(s) that warrants discontinuation, as judged by the 
Investigator and/or Insmed Medical Director 
3. A major protocol deviation, which in the opinion/discretion of the Investigator and/or 
Insmed, compromises the data integrity of the study 
4. Participant is noncompliant with the study drug treatment (defined as <80% compliance 
after at least 2 reeducation efforts)  
5. Withdrawal by participant 
6. Termination of the study by the Sponsor 
7. Investigator discretion 
8. Participant lost to follow-up 
9. Participant pregnancy 
10. Skin events (Section 8.2.7.1) 
11. Periodontal criteria met (Section 8.2.7.2)  

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12. Diagnosis of a malignancy during study, excluding carcinoma in situ of the cervix, or 
squamous or basal cell carcinoma of the skin  
13. Serious infection (Section 8.2.7.3), defined as any infection (other than associated with a 
PE) that: 
− Requires parenteral treatment with an antibiotic requiring admission to the 
hospital or parenteral treatment with an antifungal, antiviral, antiparasitic, or 
antiprotozoal agent 
− Is an opportunistic infection, such as TB or other infection whose nature or course 
may suggest an immunocompromised status 
− If a participant requires oral antibiotics to treat acute pulmonary symptoms, 
pneumonia, or any other infection, discontinuation/withdrawal from the study will 
be determined by the Investigator  
14. Participants who develop neutropenia defined as ANC <1000/mm3 
15. Participants who develop any of the stopping rules for liver safety defined in 
Section 10.6. 
7.2. 
Lost to Follow up 
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. 
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit: 
The site must attempt to contact the participant and reschedule the missed visit as soon as 
possible and counsel the participant on the importance of maintaining the assigned visit schedule 
and ascertain whether or not the participant wishes to and/or should continue in the study. 
Before a participant is deemed lost to follow up, the Investigator or designee must make every 
effort to regain contact with the participant (where possible, 3 telephone calls and, if necessary, a 
certified letter to the participant’s last known mailing address or local equivalent methods). 
These contact attempts should be documented in the participant’s medical record. 
Should the participant continue to be unreachable, he/she will be considered to have withdrawn 
from the study.  
“Lost-to-follow-up” should be marked only in an exceptional case when all documented attempts 
to reach the participant by the Investigator or other staff members were unsuccessful. 
 

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8. 
STUDY ASSESSMENTS AND PROCEDURES 
Study procedures and timing are summarized in the SoA. Protocol waivers or exemptions are not 
allowed. 
Immediate safety concerns should be discussed with the Sponsor immediately upon occurrence 
or awareness to determine if the participant should continue or discontinue study drug. 
Adherence to the study design requirements, including those specified in the SoA, is essential 
and required for study conduct. 
All screening evaluations must be completed and reviewed to confirm that potential participants 
meet all eligibility criteria. The Investigator will maintain a screening log to record details of all 
participants screened and to confirm eligibility or record reasons for screening failure, as 
applicable. 
The maximum amount of blood collected from each participant over the duration of the study, 
including any extra assessments that may be required, will not exceed 6 mL.  
Sputum sample collection will be attempted on all participants able to provide a sample either 
spontaneously, with chest physiotherapy, or by induction. Although sputum collection is an 
important exploratory PD analysis, in light of the potential challenges obtaining an adequate 
sample due to the concomitant administration of CFTR modulators, sputum collection will be 
attempted on all participants per local practice, however, sputum collection will not be required 
for participants who cannot provide sputum. Sputum sample collection will be prioritized for PD 
analyses, and if there is sample remaining, microbiology will be assessed.  
The study centers may use their own sputum induction protocols or the sputum induction 
guidelines provided in Appendix Section 10.5.  
8.1. 
Safety Assessments 
Planned timepoints for all safety assessments are provided in the SoA, Section 1.3. 
8.1.1. 
Physical Examinations 
The complete physical examination includes assessment of the head (external), eyes, ears, nose, 
throat, mouth (including gums and teeth), lungs, cardiovascular system, abdomen, 
musculoskeletal system, skin, lymph nodes, and central nervous system. Investigators should pay 
special attention to clinical signs related to previous serious illnesses. 
8.1.2. 
Vital Signs 
Vital signs will be taken before blood collection for laboratory tests. Vital signs include body 
temperature (°C), pulse (bpm), respiratory rate (breaths/min), blood pressure (systolic over 
diastolic [mm Hg]), and oxygen saturation (SpO2). Blood pressure will be assessed after the 
participant has been seated for 5 minutes. Clinically significant abnormal values of vital signs 
will be recorded as an AE. 
8.1.3. 
12-Lead Electrocardiograms 
A 12-lead ECG will be performed as indicated in the SoA, Section 1.3.  

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Refer to Section 7.1.1 for QTc withdrawal criteria and any additional QTc readings that may be 
necessary. 
8.1.4. 
Clinical Safety Laboratory Assessments 
Clinical safety laboratory assessment parameters are provided in Table 3. 
Table 3: 
Clinical Laboratory Parameters 
Category 
Laboratory Parameters 
Clinical Chemistry 
Sodium, chloride, potassium, CO2, magnesium, calcium, glucose, phosphate, 
total bilirubin (with direct and indirect fractionation, if total bilirubin is elevated 
>2 ULN), alkaline phosphatase, LDH, AST, ALT, albumin, total protein, 
creatinine, urea-nitrogen, uric acid, eGFR from the Chronic Kidney Disease - 
Epidemiology Collaboration equation formula (Section 8.1.5)  
Hematology 
Hemoglobin, erythrocytes, hematocrit, MCH, MCV, MCHC, leukocytes, 
differential blood count of neutrophils, eosinophils, basophils, monocytes, 
lymphocytes, and platelets 
Coagulation 
Prothrombin time, PTT, aPTT, and INR 
Urinalysis 
Qualitative analysis of glucose, ketones, nitrites, protein, pH, leukocytes, blood, 
bilirubin, specific gravity; microscopic examination for cells, casts, and bacteria 
Special Tests 
For women ≤45 years of childbearing potential, an additional confirmatory 
testing of FSH level with a threshold of >40 mIU/mL is required at Screening 
ALT=alanine aminotransferase, aPTT=activated partial thromboplastin time, AST=aspartate aminotransferase, 
CO2=carbon dioxide, eGFR = estimated glomerular filtration rate, FSH=follicle-stimulating hormone, INR= 
international normalized ratio, LDH=lactate dehydrogenase, MCH=mean corpuscular hemoglobin, MCHC=mean 
corpuscular hemoglobin concentration, MCV=mean corpuscular volume, PTT=partial thromboplastin time, 
ULN=upper limit of normal. 
The Investigator must review the laboratory report, document this review, and record any 
clinically significant changes occurring during the study as an AE. The laboratory reports must 
be filed with the source documents.  
Laboratory abnormalities are usually not recorded as AEs or SAEs. Abnormal laboratory 
findings (such as clinical chemistry, hematology, or urinalysis) or other abnormal assessments 
(physiologic tests such as ECGs or vital signs) that are associated with signs and/or symptoms, 
are considered clinically significant in the judgment of the Investigator, or require therapeutic 
intervention, or lead to discontinuation of the administration of study drug, must be recorded as 
AEs or SAEs if they meet the definitions of an AE (or SAE). 
All laboratory tests with values considered clinically significantly abnormal during participation 
in the study should be repeated until the values return to normal or baseline, or are no longer 
considered clinically significant by the Investigator or Medical Monitor. 
If clinically significant values do not return to normal/baseline within a period of time judged 
reasonable by the Investigator, the etiology should be identified and the Sponsor notified. 
All protocol-required laboratory tests, as defined in Table 3, must be conducted in accordance 
with the Laboratory Manual and the SoA (Section 1.3). 

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If laboratory values from non-protocol-specified laboratory tests performed at the institution’s 
local laboratory require a change in participant management or are considered clinically 
significant by the Investigator (eg, SAE or AE or dose modification), then the results must be 
recorded. 
8.1.5. 
Estimated Glomerular Filtration Rate 
The eGFR calculation per CKD-EPI equation will be analyzed for each participant who is 
≥18 years at Visit 1 (Screening), at Day 1 (Baseline), and Day 28 (EOT). 
The CKD-EPI equation described below will be used to calculate the eGFR of creatinine 
clearance in mL/min:   
GFR = 141 × min (Scr/κ, 1) α × max (Scr/κ, 1)-1.209 × 0.993Age × 1.018 [if female] × 1.159 
[if Black] 
where: 
Scr is the serum creatinine in mg/dL, 
κ is 0.7 for females and 0.9 for males, 
α is -0.329 for females and -0.411 for males, 
min indicates the minimum of Scr/κ or 1,  
max indicates the maximum of Scr/κ or 1. 
8.1.6. 
Pregnancy Testing and Contraception 
Serum pregnancy test will be conducted for WOCBP at Screening; all WOCBP must have a 
negative serum pregnancy test before randomization. 
Urine pregnancy tests will be conducted on Day 1, Day 14, Day 28, and Day 35 and at the Early 
Discontinuation Visit (if applicable).  
For all participants of childbearing potential, all methods of contraception, including abstinence, 
must be in use from Day 1 through the Day 56 EOS Visit, and for at least 90 days after the last 
dose of study drug.  
Participants who are not sexually active during the Screening Period must agree to the 
contraceptive requirements if they become sexually active with a partner of the opposite sex 
during the study and for at least 90 days after the last dose of study drug. The contraceptive 
requirements for participants are as follows: 
Male participants who can father a child must agree to use 1 highly effective method of 
contraception from Day 1 to at least 90 days after the last dose. Acceptable methods include true 
abstinence (refraining from heterosexual intercourse during the study), combined (estrogen and 
progestogen containing) or progestogen-only hormonal contraception associated with inhibition 
of ovulation, intrauterine devices, intrauterine hormone releasing systems.  
Male participants with pregnant or non-pregnant WOCBP partners must use a condom.  
Female participants must be postmenopausal (defined as no menses for 12 months without an 
alternative medical cause), surgically sterile, or using highly effective contraception methods 
(ie, methods that alone or in combination achieve <1% unintended pregnancy rates per year 
when used consistently and correctly) from Day 1 to at least 90 days after the last dose. Such 

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methods include true abstinence (refraining from heterosexual intercourse during the study), 
combined (estrogen and progestogen containing) or progestogen-only hormonal contraception 
associated with inhibition of ovulation and supplemented with a double barrier (preferably male 
condom), intrauterine devices, intrauterine hormone-releasing systems, or vasectomized partner. 
For women ≤45 years of childbearing potential, an additional confirmatory testing of FSH level 
with a threshold of >40 mIU/mL should be performed to be considered infertile. 
Note: Abstinence is only considered to be a highly effective method of contraception when this 
is the preferred and usual lifestyle of a participant. Periodic abstinence (calendar, symptothermal, 
postovulation methods), withdrawal (coitus interruptus), spermicides only, and lactational 
amenorrhea method are not acceptable methods of contraception.  
8.2. 
Adverse Events, Serious Adverse Events, and Other Safety 
Reporting 
The definitions of AEs, TEAEs, and SAEs can be found in Section 10.3.  
AEs will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or the 
participant's legally authorized representative). Adverse events may be solicited or unsolicited. 
Solicited and unsolicited AEs are defined in Section 10.3. 
The Investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible for following 
up all AEs. 
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Section 10.3. 
8.2.1. 
Time Period and Frequency for Collecting AE and SAE Information 
All AEs and SAEs will be collected continuously from the signing of the ICF until the Day 56 
EOS Visit as specified in the SoA (Section 1.3). Medical occurrences that begin after obtaining 
informed consent but before study drug administration will be recorded as medical 
history/current medical conditions, not as AEs; however, SAEs that occur after signing the ICF 
and before the first dose of study drug is administered, must be recorded and reported as SAEs. 
All SAEs will be recorded and reported to the Sponsor or designee immediately and under no 
circumstance should this exceed 24 hours, as indicated in Section 10.3. The Investigator will 
submit any updated SAE data to the Sponsor within 24 hours of it being available. 
Investigators are not obligated to actively seek information on AEs or SAEs after conclusion of 
the study participation. However, if the Investigator learns of any SAE, including a death, at any 
time after a participant has been discharged from the study, and he/she considers the event to be 
reasonably related to the study drug or study participation, the Investigator must promptly notify 
the Sponsor. 
8.2.2. 
Method of Detecting AEs and SAEs 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the participant is the preferred method to inquire about 
AE occurrences. 

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8.2.3. 
Follow-Up of AEs and SAEs 
After the initial AE/SAE report, the Investigator is required to proactively follow each 
participant at subsequent visits/contacts. All SAEs, and AESIs (as defined in Section 8.2.7), will 
be followed until resolution, stabilization, the event is otherwise explained, or the participant is 
lost to follow-up (as defined in Section 7.2).  
 
At the EOS, all ongoing AEs will be assessed by the investigators to determine whether they are 
resolved and stable or not clinically significant and reported in the appropriate eCRF page. Any 
study-related safety issues or serious events that extend past Study Day 56 (EOS) will be 
followed to resolution. 
 
Further information on follow-up procedures is provided in Section 10.3. 
8.2.4. 
Regulatory Reporting Requirements for SAEs 
Prompt notification by the Investigator to the Sponsor of an SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of a study 
drug under clinical investigation are met. 
Insmed has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study investigational medicinal product (IMP) under 
clinical investigation. This study is being conducted in the US only; regulatory requirements 
relating to safety reporting to the US FDA, IRBs, and Investigators will be followed. 
An Investigator who receives an Investigator safety report describing an SAE or other specific 
safety information (eg, summary or listing of SAEs) from the Sponsor will review and then file it 
along with the Investigator’s Brochure, or other documents and will notify the IRB, if 
appropriate according to local requirements. 
Investigator safety reports must be prepared for SUSARs according to local regulatory 
requirements and Insmed policy and forwarded to Investigators as necessary. No serious adverse 
reactions are considered expected for brensocatib. Please refer to the Reference Safety 
Information in the Investigator’s Brochure. 
8.2.5. 
Pregnancy 
Details of all pregnancies that occur in WOCBP participants within 90 days after study drug 
administration will be collected. Male participants with WOCBP partners must continue to use 
contraception for at least 90 days after study drug administration and report any pregnancies that 
occur within that time period.  
If a pregnancy is reported, the Investigator will record pregnancy information on the appropriate 
form and submit it to Insmed within 24 hours of learning of the pregnancy in a female participant 
or female partner of a male participant and after obtaining the necessary signed informed consent 
from the female partner. 
While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication or 
elective termination of a pregnancy for medical reasons will be reported as an AE or SAE. 

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Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered SAEs and will be reported as such. 
The pregnant participant/pregnant female partner of a male participant will be followed to 
determine the outcome of the pregnancy. The Investigator will collect follow-up information on 
the pregnant participant/pregnant female partner of a male participant and the neonate and the 
information will be forwarded to Insmed. 
Any poststudy pregnancy-related SAE considered reasonably related to the study drug by the 
Investigator will be reported to Insmed as described in Section 10.3.4. While the Investigator is 
not obligated to actively seek this information in former study participants who are pregnant or 
pregnant female partners of former male participants, he or she may learn of an SAE through 
spontaneous reporting. 
Any female participant who becomes pregnant while participating in the study, prior to study 
drug administration, will be discontinued from the study. 
8.2.6. 
Cardiovascular and Death Events 
Cardiovascular and death events must be reported as AEs/SAEs per the reporting instructions in 
Section 10.3. 
8.2.7. 
Adverse Events of Special Interest 
Adverse events of special interest (AESI) are defined as events known as related to treatment 
with DPP1 inhibitors. The AESI category groups and preferred terms include the following: 
hyperkeratosis (Section 8.2.7.1), periodontal/gingival events (Section 8.2.7.2), and infection 
(Section 8.2.7.3). 
8.2.7.1. 
Hyperkeratosis 
At each study visit the Investigator (or designated healthcare professional in case of a public 
health emergency) will perform a careful skin evaluation, especially of the palmar and plantar 
surfaces, the dorsal surfaces of the hands and feet, the Achilles tendon area, knees, and elbows. If 
there are any signs or symptoms of hyperkeratosis or erythema or deterioration of the preexisting 
conditions that warrant further evaluation upon Investigator discretion, the participant will be 
referred to a dermatologist for further assessment. The skin evaluation by the dermatologist for 
the participant should then be assessed thereafter on an interval per the dermatologist discretion 
until the end of the study. 
Skin exfoliation or signs of skin thickening in the palms, soles, dorsum of the hands and feet, 
Achilles tendon area, knees, or elbows should warrant evaluation by the dermatologist. 
Decisions to discontinue the participant from the study will be made by the Investigator after 
consulting with the dermatologist. Upon receiving the dermatologist’s evaluation, the 
Investigator should decide whether to continue the participant in the study or initiate early 
discontinuation of the participant. 

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8.2.7.2. 
Periodontitis/Gingivitis 
Participants will be advised to conduct self-monitoring of their oral soft tissue, gingiva, and tooth 
mobility and to report any findings. Occurrence of periodontitis/gingivitis during the study will 
be considered an AESI.  
In the case of suspected periodontitis/gingivitis, participants will be referred to a 
dentist/periodontist for evaluation, diagnosis, and treatment.  
Participants will be discontinued from the trial if they develop severe periodontal disease as 
defined by: 
• Pocket depth measurement and attachment loss ≥6 mm on 2 or more teeth 
• Have Class 3 mobility or Class 3 furcation involvement 
8.2.7.3. 
Other Infections 
Participants will be monitored throughout the study for potential infections. Severe infections, 
such as any infection requiring treatment with parenteral antibiotics/antiviral/antifungal agent, 
any clinical endoparasitosis, any opportunistic infection, should be reported as AESIs. Generally, 
all uncommon, atypical, peculiar, or unusually persistent infections should be reported as AESIs. 
Pneumonia will be a specific subcategory that will be monitored through the study. 
8.3. 
Pharmacokinetic Assessments 
The schedule for PK assessments and sampling windows is shown in the SoA, Section 1.3. 
8.3.1. 
PK Sample Collection 
Blood samples of approximately 6 mL each will be collected for measurement of plasma 
concentrations of brensocatib and for PK analysis. The total blood volume collected per 
participant (plasma drug concentration for PK analysis) will be approximately 114 mL or ~ 8 
tablespoons. 
A maximum of 2 samples may be collected at additional timepoints during the study if an SAE 
occurs or at early termination.  
Each PK plasma sample will be divided into 2 aliquots (1 for PK analysis and the other for 
backup). All samples will be stored frozen (–70°C) until shipment and then stored at –70°C until 
analysis. If a –70°C freezer is unavailable, PK samples can be stored at –20°C. The actual date 
and time (24-hour clock time) of each sample will be recorded. 
Full instructions for the collection and handling of PK samples will be provided by Insmed in a 
separate Laboratory Manual. 
8.3.2. 
PK Analysis 
Individual PK parameters of brensocatib will be determined using noncompartmental analysis 
for the following parameters: Cmax, tmax, Cmin, AUC0-24, AUClast, AUC0–∞, CL/F, Vd/F, t½ , 
Rac(Cmax), and Rac(AUC) on Day 1 and Day 28, as appropriate. Ctrough on Day 2, Day 14, Day 28, 
and Day 29 will be evaluated by statistical descriptive values (Section 9.4.2).  

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Among the PK parameters, the primary endpoints for PK evaluation will be Cmax, Tmax, AUC0-24 
and t1/2 on Days 1 and 28. All PK parameters are described in Table 4. 
Table 4: 
Pharmacokinetic Parameters 
Parameter 
Definition 
AUC0-∞ 
Area under the concentration-time curve from time 0 to infinity 
AUC0-24 
Area under the concentration-time curve from time 0 to 24 hours postdose 
AUClast 
Area under the concentration-time curve from time 0 to the last timepoint with 
measurable concentration 
CL/F 
Apparent total clearance of drug from plasma after extravascular administration 
Cmax 
Maximum plasma concentration 
Cmin 
minimum plasma concentration 
Ctrough 
plasma concentration before the next dose 
Rac(AUC) 
Accumulation ratio based on AUC at steady state (AUC0-24 ratio between Day 28 and 
Day 1) 
Rac(Cmax) 
Accumulation ratio based on Cmax at steady state (Cmax ratio between Day 28 and Day 1) 
t½ 
Elimination half-life 
tmax 
Time to maximum plasma concentration  
Vd/F 
Apparent volume of distribution 
8.3.3. 
Pharmacokinetic and Pharmacodynamic Evaluations 
Relationships between PK (brensocatib dose and exposure) and PD effects (eg, NE 
concentrations in blood and sputum, ppFEV1) and safety (eg, AESI, including hyperkeratosis, 
periodontitis/gingivitis, and infections) will be explored and the results may be reported 
separately. 
8.4. 
Pharmacogenomics 
Pharmacogenomic analyses are not included in this study. 
8.5. 
Biomarkers 
Collection of biological samples for biomarker research is also part of this study. The following 
samples for biomarker research are required and will be collected from all participants in this 
study as specified in the SoA: 
• Blood (6 mL sample per PD collection timepoint) 
• Sputum (3 mL sample per PD collection timepoint) 
• The total blood volume per participant collected over the course of the study for PD 
analysis will be approximately 42 mL or ~3 tablespoons. 

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Samples will be tested for the effect of brensocatib compared with placebo on the concentration 
of NE, CatG, and PR3 over the 4-week treatment period and 1 week after the treatment, to 
evaluate the relationship between study drug dose, AUC, and biomarker activity. 
8.6. 
Sputum Assessments 
Collection of sputum samples for microbiology assessment is also part of this study. The 
following samples will be collected from all participants in this study as specified in the SoA:  
• Sputum (3 mL sample per PD collection timepoints; PD assessments will be prioritized, 
and any remaining sputum sample will then be used for microbiology assessment) 
8.7. 
Medical Resource Utilization and Health Economics 
Medical Resource Utilization and Health Economics parameters are not evaluated in this study. 
8.8. 
Efficacy Assessments 
The schedule for efficacy assessments is shown in the SoA, Section 1.3 
8.8.1. 
Spirometry 
Spirometry assessments include the following: prebronchodilator FEV1, prebronchodilator 
ppFEV1, FVC, FEF(25-75%), and PEFR. 
Prebronchodilator PFT by spirometry (FEV1, ppFEV1, FVC, PEFR, and FEF[25-75%]) will be 
performed per the ATS/ERS criteria (Miller et al., 2005). Participants will be provided with 
detailed instruction on how to conduct the FVC maneuver per ATS/ERS spirometry 
standardization before performing the test. Time of the last bronchodilator medication use before 
the procedure will be recorded. 
The administration of a bronchodilator as part of a chronic and stable regimen is not prohibited. 
Spirometry should be performed preferably in the morning (AM) at approximately the same time 
each visit. The same spirometer and standard spirometric techniques, including calibration, will 
be used to perform spirometry at all visits and, whenever possible, the same person should 
perform the measurements. Pulmonary function tests will be performed with the participant in a 
sitting position; however, if necessary to undertake the testing with the participant standing or in 
another position, this should be noted on the spirometry report. For any participant, the position 
should be consistent throughout the study. Three (3) measurements fulfilling the ATS 
acceptability and repeatability criteria should be obtained at every visit. The acceptability criteria 
must be applied before the repeatability criteria. Unacceptable maneuvers must be discarded 
before applying the repeatability criteria. If a participant fails to provide repeatable maneuvers, 
an explanation should be recorded in the source documentation. At least 2 acceptable curves 
must be obtained. The largest FEV1 and largest FVC should be recorded after the data are 
examined from all of the acceptable curves, even if they do not come from the same curve. The 
FEF(25-75%) should be obtained from the single curve that meets the acceptability criteria and 
gives the largest sum of FVC plus FEV1 (best test). Automated best efforts, which combine 
FEV1 and FVC are not acceptable. The spirometer must be calibrated following the principles of 
the ATS/ERS guidelines every day that a study participant is assessed and spirometry is carried 

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out. The calibration records should be kept in a reviewable log. It is preferred that the calibration 
equipment (ie, 3-L syringe) that is used to calibrate the spirometer be subjected to a validated 
calibration according to the manufacturer’s specifications. 
Participants should be advised to rest at least 30 minutes and not to eat a large meal for at least 
2 hours prior to the test. If a participant is scheduled to have pulmonary rehabilitation on the day 
of their visit, they should be advised to have the PFT done before the rehabilitation on that day.  
Detailed instruction on how to conduct the spirometry and document the results are provided in a 
separate Spirometry Manual. 
8.8.2. 
Cystic Fibrosis Questionnaire – Revised 
The CFQ-R (Henry et al., 2003) is a disease-specific HRQOL measure for children, adolescents, 
and adults with CF. It is a profile measure of HRQOL with 9 QOL domains (Physical 
Functioning, Vitality, Emotional State, Social Limitations, Role Limitations/School 
Performance, Embarrassment, Body Image, Eating Disturbances, Treatment Constraints) that 
assess the impact of CF on overall health, daily life, and perceived well-being. There are 
3 symptom scales: weight, respiratory, and digestion. Scores range from 0 to 100, with higher 
scores indicating better health. The CFQ-R questionnaire should be performed before any other 
study procedures. 

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9. 
STATISTICAL CONSIDERATIONS 
9.1. 
Statistical Hypotheses 
No statistical hypotheses will be evaluated in this study. 
Primary, secondary, and exploratory objectives and corresponding endpoints are described in 
Section 3.  
9.2. 
Sample Size Determination 
Overall, the study will enroll approximately 25 to 34 participants. The 10 mg, 25 mg, and 40 mg 
cohorts will enroll approximately 7 participants each, and the placebo cohort will enroll 
approximately 4 participants. For the active treatment cohorts, there will be 2 strata: 
approximately 5 participants who have previously received and will continue to receive CFTR 
modulators as concomitant medication and 2 participants who have either never previously 
received CFTR modulators or have not been administered CFTR modulators within 30 days 
prior to Screening (visit 1) and will not receive CFTR modulators during the study 
(non-modulator stratum). For the placebo cohort, approximately 3 participants will be 
randomized into the CFTR modulator stratum and 1 participant in the non-modulator stratum. 
Each cohort will enroll participants in a 5:1 ratio (active : placebo) for the on CFTR modulator 
stratum. For the non-modulator stratum, approximately 6 participants will be randomized to 
receive active treatment (10 mg, 25 mg and 40 mg brensocatib) and 1 participant to placebo. 
If there are no safety issues observed in the first 3 dose cohorts, a 65 mg dose cohort will be 
similarly randomized: 7 participants (5 participants CFTR modulator and 2 participants 
non-modulator stratum) in active treatment and 2 participants in placebo (1 participant each in 
the CFTR modulator and non-modulator strata), increasing the sample size from approximately 
25 to 34 participants. 
A formal sample size calculation has not been performed. The number of participants has been 
chosen based on feasibility, as is typical and standard for such multiple ascending doses study 
designs and is considered sufficient to meet the study objectives. 
AUC0-24 and Cmax will be summarized by dose group and by dose group within each stratum 
(CFTR modulator and non-modulator) using the GM. The precision, as measured by the width of 
CIs, for these GMs will depend on the observed variability and sample size. The following tables 
present descriptions of 95% CIs for a range of possible values of CV(%) of the GM. Table 5 
presents participants treated with brensocatib per dose group (N=10 and N=7), and Table 6 
presents participants treated with brensocatib per stratum (N=5) (CFTR modulator) within dose 
group. 
 
 

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Table 5: 
95% CIs for Values of Inter-Participant CV(%) of the AUC0-24 and Cmax GM 
in Each Actively Treated Cohort 
N 
Geometric CV(%) 
Geometric Mean 95% 
CI LL 
Geometric Mean 95% 
CI UL 
 
30 
GM÷1.234 
GM×1.234 
10 
40 
GM÷1.317 
GM×1.317 
 
50 
GM÷1.402 
GM×1.402 
 
30 
GM÷1.312 
GM×1.312 
7 
40 
GM÷1.428 
GM×1.428 
 
50 
GM÷1.548 
GM×1.548 
Note: Assumes N=number of participants treated with brensocatib per dose group.  
CV = percent coefficient of variation, CI = confidence interval, GM = geometric mean, LL = lower limit, 
UL = upper limit. 
Table 6: 
95% CIs for Values of Inter-Participant CV(%) of the AUC0-24 and Cmax GM 
for Each Stratum Within Each Actively Treated Cohort 
Geometric CV(%) 
Geometric Mean 95% CI LL 
Geometric Mean 95% CI UL 
30 
GM÷1.440 
GM×1.440 
40 
GM÷1.613 
GM×1.613 
50 
GM÷1.798 
GM×1.798 
Note: Assumes N=5 (number of participants treated with brensocatib per stratum in each dose group). 
CV = percent coefficient of variation, CI = confidence interval, GM = geometric mean, LL = lower limit, 
UL = upper limit. 
The range of values for GM CV(%) is based on the results of Day 29 AUClast and Cmax in a study 
of patients with NCFBE (INS1007-201) and on the results of Day 28 AUC0-24 and Cmax in a 
multiple-dose study of healthy volunteers (D6190C00001). 
For the primary evaluation of safety, N=10 or 7 participants per brensocatib dose group provides 
80% or 68% probability, respectively, to detect an AE that occurs with an incidence rate of 15%, 
and 90% or 80% probability, respectively, to detect an AE that occurs with an incidence rate of 
21%. 
9.3. 
Analysis Sets 
The following analysis populations will be applied to this study. 
• Randomized Population: All randomized participants. 
• Intent-to-Treat Population: All randomized participants who receive at least 1 dose of 
study drug with at least 1 predose and 1 postdose efficacy measure. 
• Safety Population: All randomized participants who receive at least one dose of study 
drug. Participants are to be included in the analysis according to the dose and study 
drug received. 
• PK Population: All randomized participants who receive at least 1 dose of brensocatib 
and have sufficient data to calculate at least 1 PK parameter.  

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• PD Population: All randomized participants who receive at least 1 dose of study drug 
or placebo with at least 1 predose and 1 postdose PD measure.  
9.4. 
Statistical Analyses 
The SAP will be finalized prior to database lock, and it will include a more technical and detailed 
description of the statistical analyses described in this section. This section is a summary of the 
planned statistical analyses of the most important endpoints including primary and key secondary 
endpoints. 
9.4.1. 
General Considerations 
There is no hypothesis-testing in this study, and no inferential statistical analyses will be 
conducted. There will be no proxy values for missing data. PK, PD, and efficacy data will be 
presented in tables, listings, and graphs as appropriate for each variable. All data will be 
summarized by treatment group (dose levels of brensocatib and pooled placebo) and by 
treatment group within strata (CFTR modulator and non-modulator) if data warrant. The Cmax 
and AUC data may be pooled data across all dose levels within each stratum if the systemic 
exposure is approximately dose proportional, and the exposure difference between CFTR and 
non-CFTR participants will be compared based on dose-normalized Cmax and AUC. Data from 
placebo participants will be excluded from PK evaluation. 
PK parameters, such as Cmax, tmax, Cmin, AUC0-24, AUClast, AUC0–∞, CL/F, Vd/F, t½, Rac(Cmax), and 
Rac(AUC), will be derived using non-compartmental analysis, as appropriate. Ctrough, the predose 
levels on Day 2, Day 14, Day 28, and Day 29, will be listed and summarized using descriptive 
statistics based on nominal timepoints.  
The frequency of TEAEs is the primary safety endpoint for this study. All safety analyses will be 
performed on the safety population. AE listings will be produced. TEAEs, SAEs, AEs leading to 
treatment and/or study withdrawal, and AESIs will be listed for each participant along with 
outcome, severity, and relatedness to study IMP. Ad hoc summaries of TEAEs may be prepared 
if the volume of data allows.  
Exploratory endpoints include PD markers (NE, CatG, and PR3 in sputum and in blood), FEV1, 
and CFQ-R Respiratory Domain Score. In addition, the relationship between brensocatib 
exposure and NE activity will be explored. 
9.4.2. 
Primary Endpoint 
Plasma concentrations of brensocatib will be listed and summarized by active dose group and by 
active dose group within strata over each scheduled sampling time, using descriptive statistics 
(including arithmetic mean, SD, median, minimum and maximum, GM with 95% CI, and CV(%) 
of the GM, as appropriate). Individual plasma concentration data versus time will be presented in 
data listings, along with graphical plots of individual and GM plasma concentration-time plots 
presented in linear and semi-logarithmic scales. 
The main PK endpoints (Cmax, tmax, AUC0-24, and t½ on Day 1 and Day 28) will be determined 
using non-compartmental analysis.  

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All plasma PK parameters, including the ones that are not included in the primary endpoint, will 
be listed and summarized using descriptive statistics. All concentrations will be listed and 
summarized using descriptive statistics based on nominal timepoints. 
A detailed SAP will be developed. The SAP will be finalized and approved by signature prior to 
the database lock to preserve the integrity of the statistical analysis and study conclusions. 
The frequency of TEAEs is a primary endpoint of this trial. Section 9.4.5.1 discusses the 
analyses of AEs. 
9.4.3. 
Secondary Endpoints 
Analysis of dose dependency for brensocatib AUC0-24, AUClast, and Cmax after single- and 
multiple-dose administration will be performed using a power law model. The log-transformed 
PK parameters will be regressed onto log-transformed dose. An estimate of the slope and 
corresponding 95% CI will be reported. In addition, pairwise comparisons of dose dependency 
among brensocatib dose levels may be performed based on dose-normalized AUC0-24, AUClast, 
and Cmax for Day 1 and Day 28. The details of the analysis will be included in the SAP. 
9.4.4. 
Exploratory Endpoints 
NE, CatG, and PR3 (in sputum and in blood) will be exploratory endpoints. The results of these 
parameters will be listed by participant and timepoint and summarized by treatment group (dose 
levels of brensocatib and pooled placebo) and by treatment group within strata (CFTR modulator 
and non-modulator, pooled data across all dose levels). Where sufficient sample sizes are 
achieved (ie, adequate sample obtained and minimum number of quantifiable concentrations), a 
linear model with appropriate covariance pattern will be fit to the exploratory endpoints and 
between-group comparisons with associated 95% CIs will be reported. 
Individual figures of NE, CatG, and PR3 versus time will be presented with all participants 
overlaid on the same plot for each dose level (spaghetti plots). Mean plots versus time will also 
be presented by treatment group (dose levels of brensocatib and pooled placebo) and by 
treatment group within each stratum (CFTR modulator and non-modulator). 
FEV1 and CFQ-R Respiratory Domain are also exploratory endpoints. These variables will be 
listed and summarized in tables by brensocatib dose levels and placebo. 
The relationship between dose and the 3 PD parameters (NE, CatG, and PR3) will be displayed 
graphically. 
Additional PK-PD evaluations will be performed in separate analyses, in which the relationship 
between brensocatib exposure (dose or AUC) and clinical measurements (PD biomarkers, 
ppFEV1 and AESI) will be explored. The results from these PK-PD analyses will be reported 
separately.  
 
Microbial species and colony forming units from sputum assessments will be listed and 
summarized by brensocatib dose levels and placebo. 
9.4.5. 
Safety Analysis 
All safety analyses will be performed on the Safety Population. 

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All safety data will be summarized by treatment received (which may differ from the randomized 
treatment arm) and for the entire safety population, using descriptive statistics. 
Participant disposition will be listed and summarized including the number of withdrawals and 
the primary reason for withdrawal. Participants excluded from any analysis sets will be listed 
including the reasons for exclusions. 
All safety data will be listed for each participant and summarized appropriately. Adverse events 
will be coded using MedDRA and summarized by SOC and PT. Additional summaries by 
severity (NCI CTCAE) and relationship to study treatment will be presented. 
All clinical safety laboratory data and vital signs will be listed and summarized including 
changes from Baseline. Any out-of-range laboratory measurements will be flagged in the 
listings. 
The analysis of the safety endpoints and their reporting will be described in more detail in the 
SAP. 
9.4.5.1. 
Adverse Events 
Adverse events will be coded using MedDRA SOC and PT. The severity of AEs will be graded 
per the NCI CTCAE v4.0. 
The number and percent of participants with AEs including those collected at early 
discontinuation will be presented by treatment group (dose levels of brensocatib and pooled 
placebo) and by treatment group within each stratum (CFTR modulator and non-modulator). The 
severity of AEs, the relationship to study drug, AEs causing study discontinuation, and SAEs 
will be similarly presented. All AEs reported during the study will be listed. Treatment-emergent 
and treatment-related AEs will be tabulated by SOC body system and organ class. Placebo from 
all treatments will be pooled and described. 
9.4.5.2. 
Clinical Laboratory Tests 
The results of hematology, blood chemistry, and urinalysis will be listed for each participant. 
Laboratory values outside the normal ranges will be flagged. If applicable, summary statistics 
(mean, range, change from Baseline) by treatment group (dose levels of brensocatib and pooled 
placebo) and by treatment group within each stratum (CFTR modulator and non-modulator) will 
be provided for each timepoint including EOT, which will summarize the last measurement for 
participants irrespective of whether they complete, discontinue early, or are lost to follow-up. 
Baseline values are defined as laboratory values from blood and urine samples collected prior to 
first dose on Day 1 (Baseline). Summary statistics of clinical laboratory values will be tabulated 
by treatment and dose. 
9.4.5.3. 
Vital Signs 
Systolic and diastolic blood pressure, pulse rate, respiratory rate, body temperature, and oxygen 
saturation will be listed for each participant. If applicable, summary statistics (mean change, 
percentage change from Baseline, and absolute change from Baseline) by treatment group (dose 
levels of brensocatib and pooled placebo) and by treatment group within each stratum (CFTR 
modulator and non-modulator) at each timepoint and EOT will be provided. Baseline values are 

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defined as vital signs collected prior to the first dose on Day 1. The AEs reported in association 
with the clinically significant abnormalities in vital signs will be presented in the relevant AE 
listings.   
 
9.4.5.4. 
Physical Examination 
Physical examination postbaseline findings that meet the criteria for an AE will be listed in the 
relevant AE listings. 
9.4.5.5. 
Electrocardiogram 
The results of the 12-lead ECG tracings will be listed for each participant. Postbaseline ECG 
results that meet the criteria for an AE will be listed in the relevant AE listings. If applicable, 
summary statistics of ECG results will be provided. 
9.5. 
Interim Analysis 
No formal interim analysis is planned for this study. 

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10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations 
10.1.1. 
Regulatory and Ethical Considerations 
This study will be conducted in accordance with the protocol and with the following: 
• Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences (CIOMS) International Ethical Guidelines 
• Applicable ICH Good Clinical Practice (GCP) Guidelines 
• Applicable laws and regulations 
The protocol, protocol amendments, ICF, Investigator’s Brochure, and other relevant documents 
must be submitted to an IRB by the Investigator and reviewed and approved by the IRB before 
the study is initiated. 
Any amendments to the protocol will require IRB approval before implementation of changes 
made to the study design, except for changes necessary to eliminate an immediate hazard to 
study participants.  
Protocols and any substantial amendments to the protocol will require health authority approval 
prior to initiation except for changes necessary to eliminate an immediate hazard to study 
participants. 
The Investigator will be responsible for the following: 
• Providing written summaries of the status of the study to the IRB annually or more 
frequently in accordance with the requirements, policies, and procedures established 
by the IRB 
• Notifying the IRB of SAEs or other significant safety findings as required by IRB 
procedures 
• Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB, and all other applicable local 
regulations 
10.1.2. 
Protocol Deviations 
The Investigator must conduct the study in compliance with the protocol as agreed to by Insmed 
and, if required, by the regulatory authority(ies), and which was given approval/favorable 
opinion by the IRB. 
The Investigator must notify the IRB of deviations from the protocol in accordance with IRB 
reporting requirements.  

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As of May 2020, due to concern regarding COVID-19, there may be restrictions to participant 
attendance at in-clinic visits or elective inpatient admissions. In the event participants are 
restricted to attend in-clinic visits, or if the participant has concern regarding travel and attending 
in-clinic visits (due to potential public health concerns), the site must contact Insmed on how to 
conduct the scheduled assessments, and decisions must be documented in the source 
documentation. Where necessary, in-clinic visits may be conducted via telemedicine link and 
home health care visits. 
10.1.3. 
Public Health Emergency Situations 
During the COVID-19 public health emergency, Insmed, IRBs, and Investigators shall follow the 
most current version of local guidance to assure the safety of study participants, maintain 
compliance with GCP, and minimize risks to study integrity. The continuity of clinical study 
conduct and oversight may require implementation of temporary or alternative mechanisms, 
which will remain in effect only for the duration of the local public health emergency. Examples 
of such mechanisms may include, but are not limited to, any of the following: telephone contact, 
virtual visits, telemedicine visits, online meetings, non-invasive remote monitoring devices, use 
of local clinic or laboratory locations, and home visits by skilled staff. The site must contact 
Insmed on how and when to implement temporary and/or alternative mechanism of scheduled 
assessments, and all decisions taken must be documented in the source documentation. 
Additionally, all temporary mechanisms utilized, and the resulting deviations from planned study 
procedures are to be documented as being related to COVID-19. 
In a situation where local health authorities declare a public health emergency while the study is 
ongoing, the suggested guidance in the following subsections must be followed. 
10.1.3.1. Continuation or Suspension of the Study 
Ensuring the safety of trial participants is paramount. Insmed, in consultation with the clinical 
investigators and IRB, will determine whether the protection of a participant’s safety, welfare, 
and rights are best served by continuing or stopping the trial at the specific site. Such decision 
will depend on specific circumstances, including the ability to conduct appropriate safety 
monitoring, the potential impact on the investigational product supply chain, and other 
considerations. 
If the decision is to continue the study, the following considerations will be taken into account: 
10.1.3.1.1. Study Recruitment 
The Insmed will communicate to the sites the decision on whether to continue or suspend 
recruitment after considering the specific circumstances of each site, recommendation by the 
IRB, and its local health authority mandates. If, due to COVID-19, study discontinuation exceeds 
the assumed rate, Insmed may allow enrollment past the assumed sample size. 
10.1.3.1.2. Participants Already Enrolled in the Study 
If the decision is to continue the participation of participants already enrolled, the following steps 
must be taken:  

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• If a participant is not able to complete a protocol specified study visit, it may be 
necessary to adjust the visit schedule, convert in-clinic visits to telemedicine visits, 
and/or postpone study procedures until the next available in-clinic study visit. If there 
is information available from previous visits (ie, laboratory assessments) that requires 
follow-up procedures or other safety assessments, the Investigator will decide if an 
on-site visit or home healthcare visit is required or whether the participant’s safety 
can be preserved by other means. 
10.1.3.1.3. Participants Infected by COVID-19 
If a participant has had a past documented mild to moderate COVID-19 infection prior to 
enrollment in the trial but the participant has recovered and the current diagnostic tests are 
negative (negative antigen by any diagnostic laboratory kit), the participant can be screened, at 
the Investigator’s discretion. Participants who experienced hospitalization, severe disease, and/or 
COVID-19 ARDS must be excluded. 
If a participant has a documented infection by COVID-19 while in the trial, the event will be 
reported as an AE or SAE, depending on the criteria. The Investigator will follow the guidance 
provided by health authorities in the treatment of those participants. 
10.1.4. 
Financial Disclosure 
The disclosed financial interest of the Investigator must be collected before Screening of the first 
participant, following study completion at the Investigator site and 1 year following overall study 
completion. The Investigator must promptly update this information if any relevant changes 
occur during this period. 
10.1.5. 
Informed Consent Process 
Before a participant’s participation in the study, it is the Investigator’s responsibility to obtain 
freely given consent, in writing, from the participant or legally acceptable representative after 
adequate explanation of the aims, methods, anticipated benefits, and potential hazards of the 
study and before any protocol-specific screening procedures or any study IMPs are administered. 
A legally acceptable representative is an individual or other body authorized under applicable 
law to consent, on behalf of a prospective participant, to the participant’s participation in the 
clinical study. An informed consent document that includes both information about the study and 
the consent form will be prepared and given to the participant. This document will contain all the 
elements required by the ICH E6 (R2) Guideline for GCP and any additional elements required 
by local regulations. The written ICF must be prepared in the local language(s) of the potential 
participant population. 
In obtaining and documenting informed consent, the Investigator must comply with the 
applicable regulatory requirements and must adhere to GCP and to the ethical principles that 
have their origin in the Declaration of Helsinki. The consent form and any revision(s) must be 
approved by the IRB prior to being provided to potential participants. 
The participant’s written informed consent (written or electronic) must be obtained prior to 
his/her participation in the study, and must be documented in the participant’s medical records, 
as required by applicable regulations. The ICF must be signed and personally dated by the 

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participant or a legally acceptable representative and by the person who conducted the informed 
consent discussion (not necessarily the Investigator). The signed ICF must be retained in 
accordance with institutional policy, and a copy of the signed consent form must be provided to 
the participant or legal representative. The date and time that informed consent was given must 
be recorded in the CRF.  
Participants who are rescreened are required to sign a new ICF. 
 
Informed consent must be obtained prior to participation in the study, including procedures to be 
performed during Screening. For example, after the participant has provided the informed 
consent, they will be instructed to report bronchodilator use upon to returning to the clinic for the 
Screening spirometry assessment. 
10.1.6. 
Protection of Participant Identification and Confidentiality 
The Investigators and Insmed will preserve the confidentiality of all participants taking part in 
the study, in accordance with GCP and local regulations. 
The Investigator must ensure that the participant’s anonymity is maintained. On the CRF or other 
documents submitted to Insmed, participants must be identified by a unique participant identifier 
as designated by Insmed. Documents that are not for submission to Insmed (eg, signed ICFs) 
must be kept in strict confidence by the Investigator. 
In compliance with ICH GCP Guidelines, it is required that the Investigator and institution 
permit authorized representatives of the company, of the regulatory agency(s), and the IRB direct 
access to review the participant’s original medical records for verification of study-related 
procedures and data. The Investigator is obligated to inform the participant that his/her 
study-related records will be reviewed by the above-named representatives without violating the 
confidentiality of the participant. 
Participant names will not be supplied to Insmed. A participant number will be recorded in the 
CRF, and if the participant name appears on any other document (eg, laboratory report), it must 
be obliterated on the copy of the document to be supplied to Insmed. All records will be kept 
confidential to the extent provided by federal, state, and local laws. The participants will be 
informed that representatives of Insmed, IRB, or regulatory authorities may inspect their medical 
records to verify the information collected, and that all personal information made available for 
inspection will be handled in strictest confidence and in accordance with local data protection 
laws. 
The Investigator will maintain a personal participant identification list (participant numbers with 
the corresponding participant names) to enable records to be identified. 
10.1.7. 
Data Protection 
Participants will be assigned a unique identifier by the Sponsor. Any participant records or 
datasets that are transferred to the Sponsor will contain the identifier only; participant names or 
any information that would make the participant identifiable will not be transferred. 
The participant must be informed that his/her personal study-related data will be used by the 
Sponsor in accordance with local data protection law. The level of disclosure must also be 

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explained to the participant who will be required to give consent for their data to be used as 
described in the informed consent  
The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the Sponsor, by 
appropriate IRB members, and by inspectors from regulatory authorities. 
10.1.8. 
Committees Structure 
An SRC will be chartered, comprising: 
• Insmed Vice President of Pipeline Programs 
• Insmed Medical Monitor for Brensocatib Clinical Development Program 
• Insmed Clinical Pharmacology Expert 
• Vice President, Drug Safety and Pharmacovigilance (or designee) 
• Principal Investigator for the study 
• And possible external expert consultants 
Participant safety will be continuously monitored by the Sponsor, which includes safety signal 
detection at any time during the study. After the first 3 cohorts (brensocatib 10, 25, and 40 mg 
QD) have completed the study, the SRC will review available data (PK and safety data [vital 
signs, clinical laboratory test values, ECGs, and AEs]) from all cohorts to determine if 
brensocatib has shown an acceptable safety and PK profile, and whether the brensocatib dose 
should be escalated to 65 mg QD as planned. 
In particular, the SRC will review the following events: 
• Any deaths, regardless of causality 
• AESIs, including hyperkeratosis, periodontal/gingival events, and infection 
Complete details can be found in the SRC charter.  
10.1.9. 
Dissemination of Clinical Study Data 
Insmed will provide study information for inclusion in national registries according to 
national/local regulatory requirements. 
Results of this study will be disclosed according to the relevant national regulatory requirements. 
10.1.10. 
Data Quality Assurance 
The Investigator/investigational site will permit study-related monitoring, audits, IRB review and 
regulatory inspections by providing direct access to source data/documents. Direct access 
includes permission to examine, analyze, verify, and reproduce any records and reports that are 
important to the evaluation of a clinical study. 

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10.1.10.1. Data Collection 
All data obtained for this study will be entered into a 21 CFR Part 11 compliant Data 
Management System provided by Insmed or its designee. These data will be recorded with an 
EDC system using CRFs. The Investigator will ensure the accuracy and completeness of the data 
reported to Insmed. All data entry, modification or deletion will be recorded automatically in an 
electronic audit trail. 
The Investigator will provide access to his/her original records to permit a representative from 
Insmed to verify the proper transcription of data. Data reported in the CRFs must be consistent 
with and substantiated by the participant’s medical record and original source documents. The 
CRF data will be monitored by Insmed or designee. The final, completed CRF Casebook for 
each participant must be electronically signed and dated by the Principal Investigator within the 
EDC system to signify that the Investigator has reviewed the CRF and certifies it to be complete 
and accurate. 
The Insmed will retain the final CRF data and audit trail. A copy of all completed CRFs will be 
provided to the Investigator. 
10.1.10.2. Study Monitoring 
Before study initiation, at a site initiation visit or at an Investigator’s meeting, a Insmed 
representative will review the protocol, CRF, Investigator’s Brochure, and any study related 
materials with the Investigators and their staff. During the study, the Insmed study monitor or its 
designee will visit the site regularly to check the completeness of participant records, the 
accuracy of entries on the CRFs, adherence to the protocol, adherence to ICH GCP and 
applicable regulatory requirements, the progress of enrollment, and to ensure that study IMP is 
being stored, dispensed, and accounted for according to specifications. 
The Investigator must give the monitor access to relevant hospital or clinical records to confirm 
their consistency with the CRF entries. Participant confidentiality will be maintained by the 
study center. The study Insmed monitoring standards require full verification for the presence of 
informed consent, adherence to the inclusion/exclusion criteria, documentation of SAEs, and the 
recording of primary activity and safety variables. Additional checks of the consistency of the 
source data with the CRFs are performed according to the study specific monitoring plan. 
10.1.10.3. Audits and Inspections 
Domestic and foreign regulatory authorities, the IRB, and an auditor authorized by Insmed may 
request access to all source documents, CRFs, and other study documentation for onsite audit or 
inspection. Direct access to these documents must be guaranteed by the Investigator, who must 
provide support at all times for these activities. Medical records and other study documents may 
be copied during audit or inspection provided that participant names are obliterated on the copies 
to ensure confidentiality. 
If an inspection is requested by a regulatory authority, the Investigator will inform Insmed, 
immediately that this request has been made. 

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10.1.10.4. Study Record Retention 
Study documents must be retained for a minimum of 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 must be retained for a 
longer period, however, if required by local regulations. No records will be destroyed without the 
written consent of Insmed. It is the responsibility of Insmed to inform the Investigator when 
these documents no longer need to be retained. 
10.1.10.5. Source Documents 
Source documentation is the point of initial recording of a piece of data. Source documents 
include all recordings of observations or notations of clinical activities and all reports and 
records necessary for the evaluation and reconstruction of the clinical study. Source documents 
provide evidence for the existence of the participant and substantiate the integrity of the data 
collected. Source documents are filed at the Investigator’s site. 
Data reported on the CRF that are transcribed from source documents must be consistent with 
the source documents or the discrepancies must be explained. The Investigator may need to 
request previous medical records or transfer records, depending on the study. Also, current 
medical records must be available. 
The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF. 
Study monitors will perform ongoing source data verification to confirm that data entered into 
the CRF by authorized site personnel are accurate, complete, and verifiable from source 
documents; that the safety and rights of participants are being protected; and that the study is 
being conducted in accordance with the currently approved protocol and any other study 
agreements, ICH GCP, and all applicable regulatory requirements. 
10.1.11. 
Study Files and Materials 
Before the start of any study related procedures, all initial documents required by ICH GCP, 
Good Pharmacoepidemiology Practice, and applicable local regulations must be available in the 
relevant files maintained by Insmed (or delegate) and the Investigator. An Investigator Study File 
prepared by Insmed (or delegate), containing all applicable documents for use at the study site, 
will be made available to the Investigator before the start of the study. A list of personnel and 
organizations responsible for conduct of the study as well as the list of Investigator-delegates 
(eg, subinvestigator) at each study site will be included in the Investigator Study File. The 
respective files will be kept and updated by Insmed (or delegate) and the Investigator, as 
applicable. 
All study documentation and materials maintained in the Investigator Study File at the study site 
must be available for inspection by Insmed’s study monitor (or delegate) to determine that all 
required documentation is present and correct. 
The study may be audited by qualified delegates from Insmed or a competent regulatory 
authority. 

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10.1.12. 
Use of Stored Samples and Data 
Stored samples will be labeled with study and participant information and secured with limited 
access and retained per protocol requirements and in accordance with the laboratory's operating 
procedures. Electronic data will be kept in password protected computers at the laboratory and 
then transferred to Insmed or CRO, as applicable, for data analysis. Samples and corresponding 
data will be tracked using the laboratory’s specimen tracking system. 
Prior Insmed and IRB approval are required before using or sharing study samples or data in 
ways not specifically specified in the study protocol during conduct of this study. 
Any loss or unanticipated destruction of samples (eg, freezer malfunction) or data (eg, loss of a 
data sheet with individually identifiable information) that violates or compromises the scientific 
integrity of study data must be reported to Insmed and the IRB. 
At any time, participants may inform the Investigator in writing that they do not wish to have 
their samples stored beyond the completion (termination) of the study. In this case, the 
Investigator will request that all known remaining samples be destroyed and report the 
disposition of samples to the requesting participants and the IRB. 
10.1.13. 
Disposition of Stored Samples and Data 
Participant samples will be secured with limited access and retained per protocol requirements 
and in accordance with the laboratory's operating procedures. Samples stored by the central 
laboratories will be labeled with the participant’s study identification information. Data will be 
kept in password protected computers at the laboratory and then transferred to the vendor for 
data analysis. Samples and corresponding data acquired will be tracked using the laboratory’s 
specimen tracking system. 
In the future, if other Investigators may wish to study these samples and/or data, they need to 
obtain Insmed approval and participant consent before any sharing of samples and/or data.  
Any loss or unanticipated destruction of samples (eg, due to freezer malfunction) or data (eg, 
loss of a data sheet with individually identifiable information) that results in a violation that 
compromises the scientific integrity of the data collected for the study will be reported to Insmed 
and the IRB 
Additionally, participants may withdraw authorization in writing to decline their sample storage 
for a period of up to 2 years beyond the duration of the study. In this case, the Principal 
Investigator will request the destruction of all known remaining samples and report what was 
done to both the participant and to the IRB. This decision will not affect the individual’s 
participation in the study. 
10.1.14. 
Study and Site Start and Closure 
Before the start of the study at each study site, Insmed’s study monitor (or delegate) shall 
confirm adequacy of the facilities by study site visit or other acceptable methods. 
The Investigator may not enroll any participant into the study before Insmed has received written 
approval or a favorable opinion from the IRB for conducting the study and a formal meeting has 
been conducted by Insmed’s study monitor (or delegate) to initiate the study. 

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10.1.14.1. First Act of Recruitment 
The study start date is the date on which the clinical study will be open for recruitment of 
participants. The first patient screened for participation in the study is considered the first act of 
recruitment. 
10.1.14.2. Study/Site Termination 
Insmed or designee reserves the right to close the study site or terminate the study at any time for 
any reason at the sole discretion of Insmed. Study sites will be closed upon study completion. A 
study site is considered closed when all required documents and study supplies have been 
collected and a study site closure visit has been performed. 
The Investigator may initiate study site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by Insmed or the Investigator may include but are 
not limited to: 
• For study termination: 
− Discontinuation of further study IMP development 
• For site termination: 
− Failure of the Investigator to comply with the protocol, the requirements of the 
IRB or local health authorities, Insmed's procedures, or GCP guidelines 
− Inadequate or no recruitment (evaluated after a reasonable amount of time) of 
participants by the Investigator 
− Total number of participants included earlier than expected 
If the study is prematurely terminated or suspended, Insmed shall promptly inform the 
Investigators, the IRBs, the regulatory authorities, and any CRO(s) used in the study of the 
reason for termination or suspension, as specified by the applicable regulatory requirements. The 
Investigator shall promptly inform the participant and must assure appropriate participant 
therapy and/or follow-up. 
10.1.15. 
Protocol Amendments 
Any substantial change or addition to this protocol requires a written protocol amendment that 
must be approved by Insmed, before implementation. Amendments significantly affecting the 
safety of participants, the scope of the investigation, or the scientific quality of the study, require 
additional approval by the applicable regulatory authority(ies) and IRBs. Copies of the 
applicable written approvals must be filed in Insmed files and Investigator site files. 
The requirements for approval must in no way prevent any immediate action from being taken 
by the Investigator or by Insmed in the interests of preserving the safety of all participants 
included in the study. If an immediate change to the protocol is felt to be necessary by the 
Investigator and is implemented by him/her for safety reasons, Insmed or its agent must be 
notified and the applicable regulatory authority(ies)/IRBs must be informed as soon as possible. 
Any other regional reporting requirements must be adhered to. 

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Amendments affecting only administrative aspects of the study do not require formal protocol 
amendments or regulatory authority/IRB approval, but the regulatory authority(ies)/IRBs must 
be kept informed of such administrative changes in accordance with country-specific 
requirements. 
10.1.16. 
Financing and Insurance 
10.1.16.1. Finances 
Prior to starting the study, the Investigator and/or institution will sign a clinical study agreement 
with Insmed. This agreement will include the financial information agreed upon by the parties. 
10.1.16.2. Reimbursement, Indemnity, and Insurance 
Reimbursement, indemnity, and insurance shall be addressed in a separate agreement on terms 
agreed upon by the parties. 
10.1.16.3. Participant Reimbursement, Liability and Insurance 
The civil liability of the involved parties with respect to financial loss due to personal injury and 
other damage that may arise as a result of this study being conducted are governed by the 
applicable legal requirement(s). 
Insmed will provide insurance to the Investigator if required by the applicable regulatory and 
legal requirement(s). 
If required by local law, participants taking part in this study will be insured against any injury 
caused by the study in accordance with the applicable regulatory and legal requirement(s). 
10.1.17. 
Publication Policy 
Any formal presentation or publication of data collected from this study will be considered as a 
joint publication by the Investigator(s) and the appropriate personnel of Insmed. Authorship will 
be determined by mutual agreement. For multicenter studies, it is mandatory that the first 
publication be based on data from all centers and analyzed as stipulated in the protocol by the 
study Insmed and statisticians, not by the Investigators themselves. Investigators participating in 
multi center studies agree not to present data gathered from a single center or a small group of 
centers before the full, initial publication, unless formally agreed to by all other Investigators and 
Insmed. 
Insmed must receive copies of any intended communication in advance of publication (at least 
15 working days for an abstract or oral presentation and 45 working days for a journal 
submission). Insmed will review the communications for accuracy (thus avoiding potential 
discrepancies with submissions to regulatory authorities), verify that confidential information is 
not being inadvertently divulged, and provide any relevant supplementary information. 
Authorship of communications arising from pooled data may include members from each of the 
contributing centers as well as the study Insmed personnel. 
At the conclusion of the study, after the data are analyzed, the results of study will be reported in 
a clinical study report. 
 

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10.4. 
Appendix 4: Contraceptive and Barrier Guidance 
Contraceptive guidance is presented in Section 8.1.6. 

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10.5. 
Appendix 5: Sputum Induction Guidelines  
Collection of good sputum samples is critical to this study. Sputum samples will be collected at 
the clinical site. To facilitate obtaining good sputum samples during the study visit at the study 
sites, sputum induction may be performed if the participant is unable to expectorate 
approximately 3.0 mL of sputum.  
Purpose 
The purpose of this guideline is to provide recommendations to the clinical sites for obtaining a 
sputum sample by induction if the participant is unable to expectorate a sputum sample on their 
own or after chest percussion.  
Required Equipment  
• Standard handheld nebulizer used at the site or the participant can be asked to bring 
the nebulizer they use at home for pulmonary hygiene 
• The nebulizer should be thoroughly disinfected to ensure no cross-contamination  
• Sputum specimen containers with label – sputum collection tube provided by central 
laboratory 
• Sodium chloride solution (saline) – 3% and 7%, and possibly 10% 
• Standard clinic supplies (eg, disinfectant/germicidal/alcohol wipes, tissues, paper 
towels) 
Procedure 
General Instructions:  
• At the study site, sputum induction should occur in a private, contained room. 
Specific processes in place at the clinic to prevent contamination and ensure 
sterilization before and after sputum induction should be followed.  
• Clinic personnel should wear gloves and a mask during the entire procedure. 
• Only 1 participant should be induced at a time. 
• All collection containers should have a sputum collection label clearly completed 
with participant identifiers, visit name, date, and time. 
• The participant should have been instructed not to eat at least within 1 hour of sputum 
induction procedure.   
• An explanation should be provided to the participant that the purpose of this 
procedure is to help him/her cough up a sputum sample and that the success of the 
procedure is dependent on the participant’s active participation.  
Inhalation and Collection Procedures: 
• The induction procedure should start by utilizing either 3% or 7% saline based on the 
Investigator’s preference. 
• Approximately 3 to 6 mL of the selected saline should be placed in the nebulizer. 

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• The participant should be sitting up or in a semi-Fowler position.  
• The participant may wear a nose clip during the nebulization. 
• The participant should breathe slowly and deeply through the nebulizer mouthpiece 
inhaling the salt water mist. Remind the participant not to breathe quickly but to have 
slow, deep breaths pausing at peak inspiration to allow deposition of particles.  
• The nebulization time is 10 minutes.   
• At the end of this time, the participant should take a few deep breaths, swallow the 
extra saliva in his/her mouth, and try to cough up a sputum sample.   
• The participant should be encouraged to cough forcefully using the deep coughing 
method and/or “huffing” cough method.  
• All sputum should be deposited in the specimen container. The container should not 
be opened until the specimen is ready to be deposited. The container should be closed 
immediately after depositing the sample.    
• The sputum sample should be approximately 3 mL – slightly below the bottom line 
(5 mL) on the collection container. 
• If a sufficient sputum sample is not collected and the participant appears to be 
tolerating the induction procedure well, the participant can complete another 10-
minute nebulization period.  
− If a second 10-minute nebulization period is required, the recommendation is to 
increase the sodium chloride concentration (ie, if 3% was used first, then 7% 
should be used for the subsequent nebulization; if 7% was used first, then 10% 
should be used for the subsequent nebulization). 
− Closely monitor the participant for tolerability issues or side effects.  
− No more than two 10-minute nebulization periods should be completed. 
• The sputum sample should be refrigerated until it is sent to the microbiology 
laboratory. 
Side Effects 
• The subject may experience side effects from the sputum induction procedure. The 
most common side effects include the following: 
− coughing 
− sore throat 
− wheezing 
− nausea 
− lightheadedness 
− headache 
− shortness of 
breath 
− chest 
tightness 
• Other possible side effects include hyperventilation or bronchospasm. For 
bronchospasm, ensure the subject receives the necessary medical management. 

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Miscellaneous 
• If the subject needs to expectorate during nebulization, turn off the nebulizer and 
allow the subject to cough up sputum into the container. If a sufficient specimen is 
not collected, the subject should then resume the nebulization to complete the 
10-minute nebulization duration.  
The subject should be encouraged to blow his/her nose as often as needed during the induction 
procedure to help prevent nasal sections from becoming mixed with sputum specimen. 
 
 
 
 

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10.6. 
Appendix 6: Liver Safety: Suggested Actions and Follow-Up 
Assessments  
Assessing Drug-Induced Liver Injury (DILI) 
The Investigator, together with the Sponsor clinical representatives, should perform the ongoing 
monitoring of standard serum liver test results, as specified in the study protocol, to assess risk of 
DILI. 
In patients with normal serum liver test results at baseline, any of the following laboratory 
criteria of serum analytes are indicative of DILI once other causes of liver injury have been 
systematically excluded. 
• ALT ≥5 × ULN or 
• ALT ≥3 × ULN, and total bilirubin >2 × ULN, and no or minimal elevations in ALP or 
• ALP ≥2 × ULN when the source of increased ALP levels is the liver. 
In patients with a pre-existing liver disease, laboratory criteria for new-onset DILI should include 
equivalent fold increases above the patient’s pre-treatment baseline levels. 
Exclusion of alternative causes of liver injury should include viral serology, serum 
autoantibodies, and liver imaging studies. 
Stopping Rules 
Dosing with study treatment should be stopped in participants with unexplained increases in 
transaminases (ALT or AST) or total bilirubin as follows: 
• ALT or AST >8 × ULN 
• ALT or AST >5 × ULN for more than 2 weeks 
• ALT or AST >3 × ULN and (total bilirubin >2 × ULN or INR >1.5) 
• ALT or AST >3 × ULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%) 
These rules should be adjusted in patients with pre-existing liver disease and abnormal baseline 
liver tests. 
Guidance for the Investigators 
• Sponsor representative/Medical Monitor should be notified of potential DILI. 
• The Medical Monitor will contact the Investigator to discuss and agree to an approach for the 
participant’s follow-up, that may include subsequent laboratory testing and diagnostic 
evaluation of alternative causes. 
• Monitor the participant until liver function test results and clinical symptoms and signs return 
to normal or to the baseline levels, regardless of whether the study drug is continued or not. 
• Clinically significant laboratory abnormalities suggestive of DILI or the alternative cause of 
DILI must be reported as AE/SAE. 
 

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10.6.1. 
Prohibited Medications 
This appendix is a supplement to Exclusion Criterion #22, which specifies: 
• Continuous use of high-dose NSAIDS is prohibited during the study through Visit 8 
(EOS) 
Comparable NSAID Dose Levels 
 
Source: https://www.ncbi.nlm.nih.gov/sites/books/NBK65646/ 
 
 

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10.7. 
Appendix 7: Protocol Amendment History 
The Protocol Amendment Summary of Changes Table for the current amendment is located 
directly before the table of contents. 
Global Amendment 1: 01 JUL 2021 
This amendment is considered to be substantial. 
Overall Rationale for the Amendment:  
The primary driver for the changes in the protocol amendment is to provide clarification for 
study procedures and address feedback from the Cystic Fibrosis Foundation /Therapeutics 
Development Network.  
Grammatical and typographical errors were corrected throughout the document.  
The summary of major changes in this amendment, compared to the original protocol, is shown 
below: 
Description of Change 
Brief Rationale 
Section Number 
Updated synopsis; added AE 
follow-up information; updated 
Objectives and Endpoints 
To clarify study procedures in 
overall design and address 
Cystic Fibrosis Foundation 
/Therapeutics Development 
Network feedback 
Section 1.1  
Updated Schedule of 
Assessments and Procedures 
table and footnotes to reflect that 
the patient related outcome tool 
CFQ-R is first study procedure 
to be performed at the scheduled 
visits, according to HA 
guidelines; added COVID-19 
rapid testing at baseline visit; 
added drug accountability visit 
To clarify study procedures and 
footnotes, and address Cystic 
Fibrosis Foundation 
/Therapeutics Development 
Network feedback 
Section 1.3  
Updated PK, PD, and ECG 
Sampling Schedule; added table 
for PK, PD, and ECG sample 
collection 
To clarify study procedures  
Section 1.3.1  
Added background information 
to elaborate on CYP isozymes 
and CYP3A4 and Pgp inhibitors 
in brensocatib exposure 
To add to background 
information  
Section 2.1  
Section 6.8  

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Description of Change 
Brief Rationale 
Section Number 
Added and updated objectives 
and endpoints 
To address feedback from 
Cystic Fibrosis Foundation 
/Therapeutics Development 
Network 
Section 3  
Updated treatment period to 
indicate when participants 
should enter the study 
To clarify study procedures 
Section 4.1.2  
Added drug accountability visit 
on Day 14 
Updated to clarify study 
procedures  
Section 4.1.2.2  
Section 6.4  
Added text referring to 
pharmacy manual and 
medication card for IP handling 
instructions 
To clarify study procedures 
Section 4.1.4  
Definition for EOT added 
To clarify study procedures 
Section 4.4  
Updated inclusion criterion 2 
To clarify study procedures 
Inclusion Criterion 2  
Updated exclusion criterion 1 
Updated exclusion criterion 1 to 
clarify severe or unstable CF as 
per Investigator’s judgement. 
Exclusion Criterion 1  
Updated exclusion criterion 5 
To describe clinically significant 
abnormalities 
Exclusion Criterion 5  
Update exclusion criterion 16 
To clarify unstable disease due 
to colonization with specific 
bacterial species. 
Exclusion Criterion 15  
Added Investigational Product 
Administration section to 
describe study drug 
administration  
To clarify study procedures 
Section 6.1  
Updated Measures to Minimize 
Bias: Randomization and 
Blinding section; updated study 
team members who may be 
unblinded  
To clarify study procedures 
Section 6.3  
Updated Prohibited 
Medications; Clarified that long-
term steroid use is >4 weeks 
To address feedback from 
Cystic Fibrosis Foundation 
Section 6.8.3  

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Description of Change 
Brief Rationale 
Section Number 
/Therapeutics Development 
Network 
Updated Participant 
Discontinuation/Withdrawal 
From Study text on participant 
discontinuation/withdrawal from 
study 
To address feedback from 
Cystic Fibrosis Foundation 
/Therapeutics Development 
Network 
Section 7.1.3  
Updated Study Assessments and 
Procedures to include sample 
volume and sputum sample 
collection description 
To clarify study procedures  
Section 8  
Updated text on physical 
examinations 
To clarify study procedures 
Section 8.1.1  
Added that clinically significant 
abnormal values will be 
recorded as an AE 
To clarify study procedures 
Section 8.1.2  
Updated text on PK sample 
collection, added blood sample 
volumes 
To clarify study procedures 
Section 8.3.1  
Updated text on biomarkers, 
added sample types and volumes 
To clarify study procedures 
Section 8.5 
Added section on sputum 
assessment 
To clarify study procedures 
Section 8.6  
Updated text on spirometry to 
remove postbronchodilator use 
To address feedback from 
Cystic Fibrosis Foundation 
/Therapeutics Development 
Network 
Section 8.8.1  
Updated text on Cystic Fibrosis 
Questionnaire – Revised to 
indicated that questionnaire 
should be performed prior to any 
other procedures 
To clarify study procedures 
Section 8.8.2  
Updated PK parameters and 
definitions of PK and PD 
populations 
To clarify study procedures and 
statistical methods  
Section 9.1  
Section 9.3  

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Description of Change 
Brief Rationale 
Section Number 
Updated sample size 
determination text  
To clarify statistical methods  
Section 9.2  
Updated primary endpoint text; 
added primary safety endpoint 
To clarify statistical methods 
and address feedback from 
Cystic Fibrosis Foundation 
/Therapeutics Development 
Network 
Section 9.4.2  
Updated secondary endpoint text To address change in secondary 
endpoints 
Section 9.4.3  
Updated exploratory endpoint 
text 
To clarify statistical methods 
and address change to 
exploratory endpoints 
Section 9.4.4  
Added sputum induction 
guidelines 
To clarify study procedures 
Section 10.5  
 
 

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11. 
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