A Phase 1/2a Dose-Escalating Study to Evaluate the Safety, Tolerability and Pharmacokinetic Effects of ARO-ENaC in Normal Healthy Volunteers and Safety, Tolerability and Efficacy in Patients With Cystic Fibrosis
Phase: PHASE1
Conditions: Cystic Fibrosis, Pulmonary
Sponsor: Arrowhead Pharmaceuticals



Arrowhead Pharmaceuticals, Inc. 
Protocol No.: AROENAC1001 
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1. 
PROTOCOL SYNOPSIS 
 
Study Title: A Phase 1/2a Dose-Escalating Study to Evaluate the Safety, Tolerability and Pharmacokinetic 
Effects of ARO-ENaC in Normal Healthy Volunteers and Safety, Tolerability and Efficacy in Patients with 
Cystic Fibrosis 
Study Number: AROENAC1001 
Phase: Phase 1 First-in-Human, Phase 2a in CF patients 
Number of Sites: Normal Healthy Volunteers (NHVs): Single site in New Zealand 
Cystic Fibrosis (CF) patients: Multiple sites in New Zealand, Australia, and the United States 
Study Treatments: 
There will be two study treatments; one active (Test Formulation) and one placebo (Reference 
Formulation) both administered by inhalation of nebulized solution. 
Test Formulation: 
The test formulation is active ARO-ENaC to be delivered by nebulized solution. The active 
pharmaceutical ingredient (API) contained in ARO-ENaC is composed of a synthetic, double-stranded, 
small interfering RNA (siRNA) duplex conjugated to an αvβ6 targeting ligand to facilitate pulmonary 
epithelial cell delivery, formulated in normal saline to be administered by inhalation of nebulized solution. 
Reference Formulation: 
The reference formulation is placebo (PBO): normal saline (0.9%) administered by inhalation of 
nebulized solution, volume matched to the corresponding ARO-ENaC dose volume. 
Study Objective: The objective of the study is to assess the safety, tolerability, pharmacokinetics of 
ARO-ENaC in normal healthy volunteers (NHVs) and patients with Cystic Fibrosis (CF). 
Primary Endpoint: 
• The incidence and frequency of adverse events over time through end of study using 
escalating multiple doses in NHVs and in CF patients. 
Secondary Endpoints: 
• Changes from pre-dose baseline in serum electrolytes in NHVs and CF patients as a safety measure. 
• Changes from pre-dose baseline in Forced Expiratory Volume (FEV1) in NHVs as a measure of 
safety. 
• Pharmacokinetics of ARO-ENaC in NHVs and in CF patients 
Exploratory Endpoints: 
• Changes from pre-dose baseline in FEV1 in CF patients 
• Changes from pre-dose baseline in lung clearance index (LCI) in CF patients 
• Changes from pre-dose baseline in the revised cystic fibrosis questionnaire (CFQ-R) in CF patients 
• Rate of pulmonary exacerbations in CF patients receiving ARO-ENaC versus PBO 
• Changes from pre-dose baseline in body mass index (BMI) in CF patients 
• Plasma metabolite identification in NHVs (reported in a separate report outside of this study) 
• Determination of urinary excretion and metabolite identification in NHVs (reported in a separate 
report outside of this study). 
• Changes from pre-dose baseline to Day 18 in expression of αENaC using bronchoscopic brush 
biopsy samples in NHVs 
• Changes from pre-dose baseline to Day 18 in expression of αENaC using bronchoalveolar 
lavage (BAL) samples in NHVs 
• Changes from pre-dose baseline to Day 18 in cytokine levels as well as cell count and 
differential in BAL fluid in NHVs 

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Study Population/Patient Number: 
Summary of Participant Profile by Cohort: 
• Cohorts 1-4: 6 (randomized 4 active: 2 PBO) NHVs per cohort, adult healthy volunteers 
• Cohort 5: 12 adult NHVs (randomized 8 active: 4 PBO); only this cohort will undergo 
bronchoscopies 
• Cohorts 2b, 3b: up to 6 (randomized 4 active:2 PBO) CF adult patients per cohort 
• Cohort 4b: up to 12 (randomized 9 active: 3 PBO) CF adult patients with baseline ppFEV1 of > 
70%. 
• Cohort 6: up to 24 (randomized 18 active: 6 PBO) CF adult patients 
NHV subjects will enroll sequentially into a total of 5 cohorts (with 6 subjects in each of cohorts 1-4 
and 12 subjects in cohort 5), randomized to receive ARO-ENaC or PBO (4 active: 2 PBO in cohorts 
1-4 and 8 active: 4 PBO in cohort 5) in a double blinded fashion. Dose escalation will occur by Data 
Safety Committee (DSC) vote after review of cumulative safety once all healthy volunteers in the 
current cohort have completed their Day 21 study visit. There will be no DSC review during cohort 5. 
Cohort 5 is added to the study for the purpose of obtaining bronchoscopic samples in NHVs. 
CF patient cohorts 2b and 3b will each enroll up to 6 patients to receive escalating multiple doses of 
ARO-ENaC or PBO. CF patient Cohort 4b will enroll up to 12 patients to receive multiple doses of 
ARO-ENaC or PBO. CF cohort 6 will enroll up to 24 patients to receive multiple doses of ARO-ENaC 
or PBO. Cohort 6 is included in the study to assess the safety and efficacy of dosing ARO-ENaC on 
days 1, 15, and 29 (as opposed to all other CF cohorts which dose on days 1/2/3 and 22/23/24). 
CF patients not indicated or not treated with CFTR modulators/correctors at baseline or CF patients on 
a stable regimen (last 2 months) of CFTR modulators/correctors are eligible. CF patients are required 
to continue their established treatment regimen for the duration of the study without any changes. Sub- 
group analysis of CF patients will be conducted according to CFTR modulator/corrector use at 
baseline. 
*Any CF patient already in Screening when a CF patient cohort has reached capacity (defined as six 
patients who have completed Day 1 in Cohorts 2b and 3b, twelve participants who have completed 
Day 1 in Cohort 4b, and twenty-four patients who have completed Day 1 in Cohort 6), may participate 
in the study up to an additional two patients per cohort. 
NHV subjects who withdraw from the study prior to collection of the final pharmacokinetic blood 
sample, for reasons other than an adverse event or otherwise due to safety, may be replaced. CF patients 
who are withdrawn or discontinue prior to EOS visit for reasons other than an adverse event, may be 
replaced. 
A maximum total of approximately 36 NHVs and up to 56 CF participants (including up to 2 extra 
patients per cohort already in Screening and not including potential replacements) may be enrolled in the 
study. 
Number of Doses: Healthy Volunteer Cohorts (Cohorts 1 through 5) will receive a single cycle of three 
doses on Days 1, 2 and 3. 
CF cohorts 2b, 3b, 4b will receive two cycles of three doses on Days 1, 2, 3 and Days 22, 23, 24. 
CF cohort 6 will receive three total doses, with one dose given on Days 1, 15, and 29. 
Study Duration: For each NHV subject in cohorts 1-5, the approximate duration of the study clinic 
visits is a maximum of 8 weeks from the beginning of the Screening period to the Day 29 End-of- 
Study (EOS) examination. 
For each CF patient, the duration of the study is approximately 20 weeks from the beginning of the 
Screening period to the Day 113 EOS examination. 
 

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Study Confinement & Study Visits: For NHVs, clinical facility confinement will be approximately 4 
days for single dose cycle administration (Day -1 through Day 4 assessments for cohorts 1-4 and Day 0 
to Day 4 for cohort 5). Subjects will be admitted to the facility on Day -1 (or Day 0 in cohort 5) and 
will undergo assessments at the facility through Day 4. After Day 4 assessments NHV participants can 
be discharged and will return to the clinical facility starting on Day 5 for outpatient visits. 
For CF patients, clinical facility confinement will be approximately 6 hours on dosing days unless 
additional monitoring at Principal Investigator (PI) discretion is needed for safety reasons. Patients will 
return to the clinical facility for outpatient visits. There is no planned overnight confinement for CF 
patients. 
Study Design/Methods: 
Normal Healthy Volunteers: 
While ARO-ENaC is intended for use in CF patients, these patients may have baseline decreased lung 
function and may suffer from frequent disease exacerbations and are frequently on multiple concomitant 
medications. For this reason, this study initially evaluates each dose level in a healthy volunteer population 
to generate a baseline understanding of safety in a population with normal physiology and without the 
confounding factor of concomitant medication use. 
For NHVs, 4 cohorts of 6 eligible subjects (4 active: 2 placebo) will be evaluated at each dose level starting 
with Cohort 1. Cohort 5 will include 12 eligible patients (8 active: 4 placebo) who will be treated with a 
dose equal to or less than that given to Cohort 4, with the purpose of collecting bronchoscopic samples to 
evaluate for αENaC mRNA knockdown. Participants who have signed an IRB/EC approved informed 
consent form and have met all  the protocol eligibility criteria during screening, will be randomized to 
receive ARO-ENaC or PBO. NHV cohorts will receive a single cycle of three doses all at a fixed dose level 
administered daily on Days 1, 2, 3. 
NHV cohorts 1-4 will begin with administration of ARO-ENaC or PBO to two sentinel participants (one 
ARO-ENaC, one PBO). Following the Day 4 evaluation in these participants, if there are no significant 
safety concerns based on PI’s judgement, the remaining participants in the cohort will be dosed. Cohort 5 
will not utilize sentinel participants as the dose evaluated in cohort 5 will be equal to or lower than doses used in 
cohorts 1-4. Dosing of participants will be staggered by at least 30 minutes such that no two participants will 
be dosed simultaneously. Blood samples will be drawn pre-dose on Day 1 for baseline measurements. 
Based on observations for all NHV subjects in each of cohorts 1-4 through Day 21, and experience from 
any other prior cohorts (e.g. all cumulative available safety data), the DSC will meet to vote on the 
following (See Fig. 1): 
1. Dose escalation to next NHV cohort 
2. Initiation of CF cohort (Cohorts 2b, 3b, 4b) when applicable per Figure 1. 
Escalation to the next highest dose level in NHVs will proceed in cohorts of 6 until the highest planned 
dose level is completed, or the trial is halted prematurely by the PI, DSC or Sponsor due to safety or other 
concerns. 
Following an affirmative vote from the DSC meeting held during NHV cohort 4 allowing the opening of 
CF Cohort 4b, NHV cohort 5 may also be subsequently opened for accrual. The primary purpose of cohort 
5 will be to assess the effect of ARO-ENaC on αENaC mRNA expression, with samples obtained via 
bronchoscopy. The dose in cohort 5 will be equivalent to or less than the dose utilized in cohort 4. Based 
on available safety data reviewed during prior DSC meetings, the Sponsor or DSC may adjust the dose in 
cohort 5 downward. 

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The DSC will consist of at least one study Investigator, Sponsor Medical Monitor, Sponsor 
pharmacovigilance lead, and an independent physician experienced in pulmonary drug development 
and/or early stage clinical trials. 
Cystic Fibrosis Patients: 
Cohorts 2b, 3b, 4b will enroll eligible CF patients who have signed an IRB/EC approved informed consent 
form to receive two cycles of ARO-ENaC or PBO administered daily on Days 1, 2 and 3, then again on 
Days 22, 23 and 24. Screening for the CF cohorts can begin once Cohort 2 dosing has commenced but 
dose administration may not proceed until after the DSC has opened the designated CF patient cohort. CF 
patient cohorts 2b, 3b, and 4b will be opened for accrual once the corresponding NHV cohort receiving 
the same dose level has reached Day 21 and based on DSC vote that it is safe to proceed. CF patient cohorts 
2b, 3b, and 4b will enroll in sequence with 2b enrolling first, followed by 3b and then Cohort 4b. 
Once all subjects in CF cohort 4b have completed the Day 29 study visit, the DSC will meet to review all 
cumulative safety data to date and to vote on the initiation of CF cohort 6. Following an affirmative vote 
from this DSC meeting, CF cohort 6 may be opened for accrual. The purpose of cohort 6 is to assess the 
safety and efficacy of an alternate dosing regimen. In CF cohort 6, the 3-day dosing cycle used in cohort 
4b is compressed to a single dose, which is given at 2 week intervals, such that subjects will be dosed on 
Days 1, 15, and 29. The dose given on each dosing day to a subject in CF cohort 6 (in respirable delivered 
dose [RDD] terms, which represents the amount of drug that reaches the lung, as opposed to the amount 
of drug loaded into the nebulizer) will be ≤ 3x the dose given on each dosing day to a subject in CF 
cohort 4b. Thus, the dose (in RDD terms) given on Day 1 to a subject in cohort 6 will be ≤ the total 
cumulative dosage given over Days 1, 2, and 3 to a subject in cohort 4b. Of note, the RDD does not scale 
identically to the nebulizer loaded dose (i.e. tripling the RDD does not necessarily result in tripling the 
nebulizer loaded dose). 
The dose escalation schedule is outlined in Figure 1. 
 
Blinding (where applicable) will be preserved to the extent possible. However, treatment un-blinding or 
un-blinding of an individual participant may occur, at the discretion of the PI or Medical Monitor where 
deemed necessary for treatment of an AE or for a decision to be made regarding trial continuation. 
After all subjects in a cohort (except cohort 6) have completed an EOS visit, Sponsor may be unblinded 
to that cohort. PI and study participants will remain blinded.  
 
Primary analysis is planned once both all subjects in cohort 6 have completed the Day 43 study visit and 
all subjects from other cohorts have completed EOS. PIs and study participants will remain blinded 
through EOS. Sponsor will be unblinded to analyze both safety and efficacy endpoints for all NHV and 
CF cohorts. Final Analysis is planned when all subjects have ended study and database is locked. Safety 
and efficacy results will be updated based on complete database in final analysis. 

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Figure 1: Dose Escalation Schedule 
 
 
 
* Cohorts 1-4 each use 2 sentinel subjects dosed before the rest of the cohort. Where specified, dose 
represents the highest dose that may be used in the cohort. The DSC or Sponsor may adjust the dose 
downward if indicated based on available safety data. 
ǂ specified dose given once on Day 1, Day 2 and Day 3 
** Cohorts 2b, 3b, 4b, and 6 enroll in sequence per Figure 1 and after associated DSC 
approval. 
Adverse event monitoring: 
Safety assessments will include AE/SAEs, chest x-rays, FEV1, physical examinations, vital sign 
measurements (blood pressure, heart rate, temperature, pulse oximetry and respiratory rate), ECGs, 
clinical laboratory tests including serum and urine electrolytes (spot urine electrolytes only 
analyzed in setting of hyperkalemia), concomitant medications/therapy, and reasons for treatment 
discontinuation. Safety assessments will be performed at specified time points and prior to study 
completion. 
The AE/SAE reporting period for an enrolled participant begins when the participant provides informed 
consent. Treatment-emergent AEs (TEAEs) and treatment-emergent SAEs are defined as those that occur 
following study drug administration or are a pre-existing condition exacerbated by study drug. The 
TEAE reporting period begins after the first dose and extends until the End-of-Study visit is complete. 
All SAEs that occur during the AE reporting period, in addition to reporting via electronic case report 
forms (eCRFs), must also be reported to the Sponsor via the SAE report form within 24 hours of being 
notified, regardless of the relationship of the AE to study treatment. All AEs will be followed until 
resolution, until the condition stabilizes, until the event is otherwise explained, or until the participant is 
lost to follow-up. If the PI learns of any SAE, including a death, at any time after a patient has been 
discharged from the study, and he/she considers the event reasonably related to the investigational 

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product, the PI will promptly notify the Sponsor. Laboratory or diagnostic (e.g. ECG) abnormalities will 
be reported as AEs if considered clinically significant by the PI. Laboratory or diagnostic assessment 
abnormalities not reported as AEs are not to be reported as Clinically Significant in the study database. 
*Any AE consistent with lower respiratory infection, dyspnea, bronchospasm, or CF exacerbation 
will trigger a chest X- ray and PFT measurement. 
Treatment Stopping Rules & Data Safety Committee: 
A decision to stop the trial early or discontinue drug in an individual subject or group of subjects may be 
indicated based on any of the following: 
1. A single Serious Adverse Events (SAE, defined in Section 11.1) considered at least possibly 
related to study drug. 
2. Two cases of a drop from baseline FEV1 (which must be confirmed on repeat within 48 hours) in 
healthy volunteer cohorts of ≥ 20% (absolute decline in % of predicted) considered to be at least 
possibly related to study drug by study investigator 
3. One case of a drop from baseline FEV1 (which must be confirmed on repeat within 48 hours) in 
cystic fibrosis cohorts of ≥ 20% (absolute decline in % of predicted) considered to be probably 
related to study drug by study investigator 
4. A post-dose increase in serum potassium to > 5.7 milliequivalents/Liter which must be from a non- 
hemolyzed sample and confirmed by repeat blood draw within 48 hours of initial  results. 
If any such events occur, within 5 days of Sponsor being notified of the event, the DSC will meet to    
review the event and determine any necessary actions as detailed below. 
Central labs will be utilized. However local labs may be utilized as necessary if needed by the 
investigator (including for Screening) or for emergent situations, including time critical analytes such as 
serum potassium and repeat clinical chemistries. 
Sponsor or PI can discontinue any subject at any time with or without DSC consultation. If such events 
(as described above) occur and the subject is not discontinued from the study the reason for not 
discontinuing the subject will be included in DSC meeting minutes. Including, but not limited to the 
events listed above, the DSC may pause the study to additional dosing or dose escalation to provide time 
to evaluate safety data and recommend the action to be taken, which may include, but is not limited to 
one of the following: 
• Discontinuation of a subject or group of subjects from the study 
• The study is stopped immediately with no further dosing 
• The study will continue until the current cohort is completed 
• The study will continue, but the next dose escalation will be to a level midway between the 
current level and the next planned level 
• The study will continue as planned 
The DSC will consist of at least the Sponsor Medical Monitor, Sponsor pharmacovigilance lead, 
one study Investigator and an independent physician experienced in Phase 1 clinical trials. 

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Study Assessments: 
Safety Assessments: 
Safety assessments will be performed at specified time points per the SOA and will include the following: 
• Vital signs: Resting heart rate, semi-supine systolic/diastolic blood pressure, respiratory rate, pulse 
oximetry and temperature 
• Clinical laboratory measurements (e.g., biochemistry, hematology, coagulation, urinalysis), urine 
electrolytes including potassium, sodium and urine FeNa (spot urine electrolytes will only be 
analyzed in the setting of hyperkalemia) 
• Resting ECG measurements (measured after participant is semi-supine for at least 3 minutes). 
• Chest X-ray (upright and lateral) 
At each visit, participants will be asked about concomitant medications/therapy and will be 
instructed to volunteer any information regarding AEs and SAEs that he/she may have experienced. 
Any known untoward event that occurs beyond the AE reporting period that the PI considers an 
SAE possibly related to study treatment will be reported to Arrowhead. 
• Spirometry conducted as per ATS/ERS guidelines 
Assessment of Pharmacodynamic Effect in NHVs:  
• αENaC expression from bronchial brushing and BAL samples (only assessed in NHV cohort 5) 
Assessments of Efficacy in CF patients: 
Results including absolute change, percent change from baseline to EOS will be analyzed and 
summarized by dose cohort and treatment group for efficacy parameters. 
Efficacy assessments will be performed at specified time points per the SOA and will include the 
following: 
• Spirometry 
• LCI  
• CFQ-R 
• Rate of pulmonary exacerbations 
• BMI 
Immunogenicity: 
Blood samples for the anti-drug antibodies test will be collected per the SOA. 
Genotype: 
Genotype will be obtained for CFTR and ENaC (where available) mutations. 
Pharmacokinetics: 
Blood samples will be collected from each subject for pharmacokinetic analysis per the SOA. 
Excretion and Metabolism: 
Blood samples will be collected from each subject for metabolic analysis per the SOA. Samples will be 
frozen at -80ºC for analysis outside of this study. 
Urine collections will be performed after dosing per the SOA. 

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Data Analysis: 
Healthy volunteers and CF patients will be analyzed separately. 
 
 For each healthy volunteers and CF population, subjects will be analyzed by cohorts. Placebo subjects    
 from each cohort will be pooled. In addition, CF patients will also be analyzed in aggregate and   
 separately based on CFTR mutation status and based on use or no use at baseline of a stable regimen  
 (last 2 months) of CFTR modulators/correctors as well as use or no use at baseline of inhaled  
 hypertonic saline. 
Screening, Compliance, Tolerability and Safety Data: 
In general, safety analyses will be performed based on Safety Analysis Set, which includes all enrolled 
subjects who receive at least one dose of study drug (placebo or active). Post-dose safety assessments 
will be compared with measurements recorded at baseline. Treatment-emergent AEs will be summarized 
using the Medical Dictionary for Regulatory Activities (MedDRA) under version 23.0 or later by System 
Organ Class (SOC) and Preferred Term (PT). The incidence and frequency of treatment-emergent AEs, 
SAEs, related AEs, related SAEs, and AEs leading to discontinuation, will be summarized by cohort per 
SOC, PT, and severity. All AEs, SAEs will also be presented in listings. The duration of AEs will be 
determined and included in listings, along with the action taken and outcome. The incidence of 
laboratory abnormalities will be assessed using descriptive summary statistics and shift tables. Vital sign 
measurements will be summarized at each scheduled time point using descriptive statistics. Abnormal 
physical examination findings will be summarized by time point and presented in subject listings. ECG 
parameters, changes from baseline, and qualitative assessments will be summarized. Pregnancy and FSH 
test results will be listed separately. 
Pharmacokinetics: 
Plasma concentrations of ARO-ENaC product constituents will be used to calculate the following PK 
parameters: 
maximum observed plasma concentration (C max ), area under the plasma concentration time curve 
(AUC) from time 0 to 24 hours (AUC 0-24 ), AUC from time 0 to the last quantifiable plasma 
concentration (AUC last ), AUC from time 0 extrapolated to infinity (AUC inf ), and terminal elimination 
half-life (t ½ ). Additional PK parameters may be calculated as needed. Pharmacokinetic parameters will 
be determined using non-compartmental methods. Descriptive statistics of PK parameters will include 
mean, standard deviation (SD), coefficient of variation, median, minimum, and maximum. PK results 
will be analyzed for dose proportionality, and sex differences. 
 
PK population: All NHVs and CF patients that received at least one dose of study drug and that have 
measurable PK concentration data. A subject may be excluded from PK summary and statistical analysis 
if the subject has a protocol deviation(s) that is thought to impact PK analysis. 
NHV Pharmacodynamic (PD) Effect Assessment: 
Results, including percent change and duration of response from baseline to EOS will be analyzed and 
summarized by cohort. The NHV PD population includes subjects in NHV cohort 5. 
 

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CF Patient Efficacy Assessments: 
Descriptive summary of ppFEV1, LCI, BMI and CFQ-R respiratory domain score at each scheduled 
study visit and change from baseline will be summarized. Events rate of pulmonary exacerbation will 
be summarized by cohort.  
Immunogenicity (Anti-Drug Antibodies): 
Shift tables will be displayed by cohort or by dose in both healthy volunteers and CF patients. 
Baseline for data analysis purposes is defined as the pre-dose value occurring closest to the first dose of 
ARO-ENaC or PBO administered in the study. 
Additional details will be provided in the statistical analysis plan. 

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2. 
TABLE OF CONTENTS 
1. 
PROTOCOL SYNOPSIS ....................................................................................................................... 2 
2. 
TABLE OF CONTENTS ...................................................................................................................... 16 
3. 
STUDY INFORMATION AND SIGNATURES ................................................................................ 19 
4. 
LIST OF ABBREVIATIONS AND TERMS ...................................................................................... 20 
5. 
INTRODUCTION ................................................................................................................................. 22 
5.1. 
Background Information ........................................................................................................ 22 
5.2. 
Mechanism of Action of ARO-ENaC & Therapeutic Rationale ........................................... 22 
5.2.1. 
siRNA Mechanism of Action ................................................................................................. 22 
5.2.2. 
ENaC Inhibition ..................................................................................................................... 23 
5.2.3. 
Combining ENaC Inhibition with CFTR Modulators ............................................................ 24 
5.3. 
ARO-ENaC Pre-Clinical Pharmacology Studies ................................................................... 25 
5.4. 
ARO-ENaC Pre-Clinical Pharmacokinetic and Product Metabolism Studies ....................... 25 
5.5. 
ARO-ENaC Pre-Clinical Toxicology Studies........................................................................ 25 
5.6. 
Rationale for the Study .......................................................................................................... 25 
5.7. 
Risk Assessment for Participants ........................................................................................... 26 
5.8. 
Justification for Doses in Humans ......................................................................................... 27 
6. 
STUDY OBJECTIVES AND ENDPOINTS ....................................................................................... 30 
6.1. 
Primary Endpoint ................................................................................................................... 30 
6.2. 
Secondary Endpoints ............................................................................................................. 30 
6.3. 
Exploratory Endpoints ........................................................................................................... 31 
7. 
STUDY PLAN ....................................................................................................................................... 31 
7.1. 
Study Design .......................................................................................................................... 31 
7.2. 
Rationale for Study Design .................................................................................................... 34 
7.3. 
DSC and Criteria for Dose-escalation and Dose Limiting Toxicities .................................... 35 
7.4. 
Stopping Rules & Data Safety Committee ............................................................................ 35 
7.5. 
Primary Analysis and Final Analysis ..................................................................................... 36 
7.6. 
Duration of the Study ............................................................................................................. 36 
8. 
PATIENT SELECTION ....................................................................................................................... 36 
8.1. 
Number of Patients ................................................................................................................ 36 
8.2. 
Inclusion Criteria ................................................................................................................... 37 
8.3. 
Exclusion Criteria .................................................................................................................. 38 
8.4. 
Participant Withdrawal Criteria ............................................................................................. 39 
8.5. 
Restrictions and Concomitant Medications ........................................................................... 40 
9. 
INVESTIGATIONAL PRODUCT ...................................................................................................... 41 
9.1. 
Description, Identification and Dosage .................................................................................. 41 
9.2. 
Study Drug Handling ............................................................................................................. 43 
9.3. 
Accountability of Study Supplies .......................................................................................... 43 
9.4. 
Retention of Investigational Product Vials ............................................................................ 44 

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9.5. 
Allocation to Treatment ......................................................................................................... 44 
9.6. 
Blinding and Code-Break ...................................................................................................... 44 
10. STUDY METHODS AND SCHEDULES ........................................................................................... 45 
10.1. 
Overview of Procedures ......................................................................................................... 45 
10.2. 
Selection and Screening ......................................................................................................... 47 
10.3. 
On-Study Procedures/Assessments ........................................................................................ 47 
10.3.1. 
Demographics/Medical History ............................................................................................. 47 
10.3.2. 
Physical Exam ........................................................................................................................ 48 
10.3.3. 
Electrocardiogram .................................................................................................................. 48 
10.3.4. 
Chest X-ray ............................................................................................................................ 48 
10.3.5. 
Vital Sign Assessments .......................................................................................................... 48 
10.3.6. 
Clinical Laboratory Tests ....................................................................................................... 48 
10.3.7. 
Spirometry, CFQ-R and Lung Clearance Index ..................................................................... 50 
10.3.8. 
Bronchoscopies ...................................................................................................................... 52 
10.3.9. 
Pharmacokinetics ................................................................................................................... 52 
10.3.10. Concomitant Medications/Therapies ..................................................................................... 53 
10.3.11. Early Termination Procedures ............................................................................................... 53 
10.4. 
Allocation of Treatment ......................................................................................................... 53 
10.5. 
Study Treatment Administration & Timing of Procedures .................................................... 53 
10.6. 
Pregnancy Testing and Contraception Requirements ............................................................ 54 
10.7. 
Safety Assessments ................................................................................................................ 54 
11. ADVERSE EVENTS ............................................................................................................................. 55 
11.1. 
Definitions ............................................................................................................................. 55 
11.2. 
Clinical Laboratory Abnormalities and Other Abnormal Assessments as AEs ..................... 56 
11.3. 
Timing, Frequency, and Method of Detecting AEs ............................................................... 56 
11.4. 
Recording of AEs ................................................................................................................... 56 
11.5. 
Evaluating AEs ...................................................................................................................... 57 
11.5.1. 
Assessment of Severity .......................................................................................................... 57 
11.5.2. 
Assessment of Causality ........................................................................................................ 57 
11.6. 
Follow-up of AEs ................................................................................................................... 58 
11.7. 
Prompt Reporting of SAEs .................................................................................................... 58 
11.7.1. 
Completion and Transmission of the SAE reports ................................................................. 58 
11.7.2. 
Pregnancy Reporting .............................................................................................................. 59 
11.7.3. 
Serious Adverse Event Reports to the IRB ............................................................................ 59 
11.8. 
Regulatory Requirements for Reporting of SAEs .................................................................. 59 
11.9. 
Post-study AEs ....................................................................................................................... 60 
11.10. 
SAEs Related to Study Participation ..................................................................................... 60 
12. DATA ANALYSIS AND STATISTICAL CONSIDERATIONS ...................................................... 60 
12.1. 
Sample Size Considerations & Stratification ......................................................................... 60 
12.2. 
Screening Data ....................................................................................................................... 61 
12.3. 
Safety/Tolerability Data ......................................................................................................... 61 

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12.4. 
Immunogenicity (Anti-drug Antibodies) Data ....................................................................... 62 
12.5. 
Pharmacokinetic Data ............................................................................................................ 62 
12.6. 
Pharmacodynamic/Efficacy Data ........................................................................................... 63 
12.7. 
Data Recording and Quality Control ..................................................................................... 63 
12.8. 
Handling Missing and Incomplete Data ................................................................................ 63 
13. STUDY APPROVAL AND CONDUCT ............................................................................................. 63 
13.1. 
Regulatory Approval .............................................................................................................. 63 
13.2. 
Ethics Committee (EC)/ Institutional Review Board (IRB) Approval .................................. 63 
13.3. 
Ethical Considerations ........................................................................................................... 64 
13.4. 
Written Informed Consent ..................................................................................................... 64 
13.5. 
Emergency Contact with Principal Investigator .................................................................... 64 
13.6. 
Notification of General Practitioner ....................................................................................... 65 
13.7. 
Clinical Laboratory Certification and Reference Ranges ...................................................... 65 
13.8. 
Protocol Deviations ................................................................................................................ 65 
13.9. 
Termination of the Study ....................................................................................................... 65 
14. STUDY ADMINISTRATION .............................................................................................................. 66 
14.1. 
Study Monitoring ................................................................................................................... 66 
14.2. 
Quality Assurance .................................................................................................................. 66 
14.3. 
Records Retention .................................................................................................................. 67 
15. INFORMATION DISCLOSURE AND INVENTIONS ..................................................................... 67 
15.1. 
Ownership .............................................................................................................................. 67 
15.2. 
Confidentiality ....................................................................................................................... 68 
15.3. 
Publication ............................................................................................................................. 68 
16. APPENDICES ....................................................................................................................................... 68 
16.1. 
Definition of Pulmonary Exacerbations (PEx) in CF Patients ............................................... 68 
16.2. 
Guideline for Evaluation and Treatment of Hyperkalemia for NHVs and CF Patients ......... 69 
17. REFERENCES ...................................................................................................................................... 70 
 

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3. 
STUDY INFORMATION AND SIGNATURES 
 
Investigator’s Statement: 
I have read and understood the information in this protocol and agree to conduct the trial 
according to the protocol (subject to any amendments) and in accordance with the 
principles of ICH E6 Good Clinical Practice guidelines. I have read and agree to comply 
with the Investigator obligations stated in this protocol, as well as with any and all 
applicable federal, state, or local laws and regulations. Any changes in procedure will only 
be made if necessary to protect the safety, rights or welfare of participants. 
I agree to conduct or to supervise the trial in person. 
I agree to ensure that all that assist me in the conduct of the study are aware of their 
obligations. 
 
Principal Investigator: 
 
 
 
Signature 
Date 
 
 
 
Printed Name 

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4. 
LIST OF ABBREVIATIONS AND TERMS 
 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
API 
Active Pharmaceutical Ingredient 
AST 
Aspartate transaminase 
ARO 
Arrowhead Pharmaceuticals, Inc. 
AUC 
Area under the curve 
AUC inf 
Area under the curve from time 0 to infinity 
BAL 
BP 
Bronchoalveolar lavage 
Blood pressure 
cGCP 
current Good Clinical Practice 
cGMP 
current Good Manufacturing Practice 
Cmax 
Concentration maximum (peak) 
CRA 
Clinical Research Associate 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
CTN 
Clinical Trial Notification 
CVA 
Cerebrovascular accident 
dL 
deciliter 
DSC 
Data Safety Committee 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
EOS 
End of Study 
FDA 
Food and Drug Administration 
FEV1 
Forced Expiratory Volume in the first second 
FSH 
Follicle-Stimulating Hormone 
GCP 
Good Clinical Practice 
GGT 
Gamma glutamyl transferase 
GLP 
Good Laboratory Practice 
GMP 
Good Manufacturing Practice 
HBV 
Hepatitis B virus 
HIV 
Human Immunodeficiency Virus 
HR 
Heart Rate 
ICH 
International Conference on Harmonisation 
IRB 
Institutional Review Board 
IWRS 
Interactive web response system 
Kg 
Kilogram 
L 
LLN 
Liter 
Lower limit of normal 
MCH 
Mean Cell Hemoglobin 
MCHC 
Mean Cell Hemoglobin Concentration 
MCV 
Mean Cell Volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
Mg 
milligram 
mmHg 
millimeters of mercury 

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NHV 
Normal healthy volunteers 
NOAEL 
No observed adverse event level 
NYHA 
New York Heart Association 
PBO 
Placebo 
PD 
Pharmacodynamic 
PI 
Principal Investigator 
PK 
Pharmacokinetic 
ppFEV1 
Percent predicted FEV1 
PT 
Prothrombin Time or Preferred Term 
PTT 
Partial thromboplastin time 
QRS 
QRS duration (complex) – a structure on the ECG that corresponds to 
the depolarization of the ventricles 
QT 
QT interval – a measure of the time between the start of the Q wave and 
the end of the T wave in the heart’s electrical cycle 
RDD 
RNA 
Respirable delivered dose 
Ribonucleic acid 
RNAi 
RNA interference 
SAE 
Serious Adverse Event 
SD 
Standard Deviation 
siRNA 
Short interfering RNA oligonucleotides 
SOA 
Schedule of Assessments 
SOC 
System Organ Class 
t1/2 
terminal elimination half-life 
TIA 
Transient Ischemic Attack 
ULN 
Upper Limit of Normal 

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5. 
INTRODUCTION 
5.1. 
Background Information 
Cystic fibrosis (CF), is caused by mutations in the CF transmembrane conductance regulator (CFTR) 
gene, which encodes a chloride and bicarbonate ion channel expressed at the apical surface of epithelial 
cells (Choi 2001; Stoltz 2015). In its wild-type form, the CFTR protein is localized on the cell surface 
and acts as a cyclic adenosine monophosphate (cAMP)-regulated ion channel (Alton 2016). The 
transport of anions (such as chloride and bicarbonate) through the apical membrane of epithelial cells 
creates an osmotic gradient for fluid secretion (Quon 2016). In the lungs, the balance of chloride ion 
secretion through functional CFTR protein and sodium absorption through the epithelial sodium 
(Na+) channel (ENaC) maintains an optimum volume, electrolyte composition, and pH of the airway 
surface liquid (a thin fluid layer protecting the epithelium from inspired air) (Hobbs 2013; Stoltz 
2015; Vallières 2014). The CFTR protein also plays an absorptive role in some epithelial structures, 
particularly exocrine glands, such as the sweat gland, pancreas, gastrointestinal tract, and in the male 
and female reproductive tract. The absence or dysfunction of the CFTR therefore results in 
dehydrated, thickened secretions that obstruct these epithelium lined ducts of exocrine tissues, 
resulting in predisposition to infection, inflammation and tissue damage (Quon 2016). 
 
As ENaC is negatively regulated by CFTR, reduced functional levels of or the absence of CFTR in 
patients with CF results in reduced chloride/bicarbonate ion and water secretion. Reduced CFTR 
function leads to ENaC hyperactivity, resulting in increased sodium ion and water absorption 
(Bangel-Ruland 2015; Hobbs 2013; Stoltz 2015) which subsequently contributes to dehydrated, 
thickened mucus. The combined effects of reduced chloride secretion (CFTR dysfunction) and 
hyperabsorption of sodium and water (ENaC hyperactivity) are dehydration of the cell surface, a 
reduction in the water content of the airway surface liquid, and thick, obstructive mucus that is 
resistant to removal (Stoltz 2015; Amaral 2015). Homeostasis of the airway surface liquid with 
adequate mucus hydration is essential for efficient mucociliary clearance of aerial pathogens, which 
is needed to maintain the sterility of the lung (Hobbs 2013; Stoltz 2015; Vallières 2014). Overly 
viscous and dehydrated mucus leads to impaired mucociliary clearance, resulting in 
infective/inflammatory sequelae, including airway mucus obstruction and disseminated 
bronchiectasis, recurrent bacterial infections, chronic inflammation, and lung damage/scarring (CFF 
Patient Registry Annual Report 2015; Maselli 2017). Finally, this cascade leads to end-stage lung 
disease, which can only be resolved by lung transplantation (Amaral 2015). Even in the setting of 
CFTR modulator/corrector therapy, there remains an unmet medical need for additional therapeutic 
options, particularly in certain sub-populations (e.g. those with Class I mutations). Additionally, 
ENaC inhibition may work synergistically with CFTR modulation (See Section 5.2.3). 
5.2. 
Mechanism of Action of ARO-ENaC & Therapeutic Rationale 
 
siRNA Mechanism of Action 
RNAi-based therapeutics have the potential to silence the expression of any gene. RNAi is a 
naturally-occurring phenomenon by which short interfering RNA oligonucleotides (siRNAs) trigger 
a sequence-specific down-modulation of gene expression. RNAi triggers refer to synthetic siRNAs 
designed to target specific gene expression (Fire 1998). 
ARO-ENaC is a synthetic, double-stranded, pulmonary epithelium-targeted RNAi trigger designed to 
VSHFLILFDOO\ VLOHQFH P51$ WUDQVFULSWV HQFRGHG E\ WKH Į(1D& JHQH XVLQJ DQ 51$ LQWHUIHUHQFH
mechanism. The RNAi trigger is a short, double-stranded RNA conjugated to an ĮYȕ LQWHJULQ
targeting OLJDQGIRUWKHĮYȕUHFHSWRUNQRZQWREHSUHVHQWRQWKHSXOPRQDU\HSLWKHOLDOFHOOV7KLV
targeting approach induces epithelial cell receptor-mediated endocytosis and introduction of the 

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double stranded RNAi trigger into the cytoplasm of epithelial cells which results in its association 
with the protein components of the RNA induced silencing complex (RISC), resulting in “on target” 
highly sequence-specific degradation of messenger RNA complementary to the antisense strand of 
the RNAi trigger. ARO-(1D&WDUJHWVWKHĮ(1D&P51$$FWLYH5,6&LVDPXOWLSOHWXUQRYHUHQ]\PH
complex, therefore, incorporation of a single RNAi trigger into RISC can result in the degradation 
of many mRNA molecules, and subsequently, prolonged reduction of the expression of the 
corresponding protein. The persistence of pharmacologic activity significantly beyond the period of 
plasma or local tissue exposure is due to this unique RNAi mechanism in which a small amount of 
guide strand can persist and be active within RISC in the cytoplasm of target cells for extended 
periods of time. 
 
siRNA mechanism of action 
 
 
 
 
ENaC Inhibition 
%\ GHOLYHULQJ 51$L WULJJHUV WDUJHWLQJ WKH Į(1D& VHTXHQFHV WR WKH SXOPRQDU\ HSLWKHOLXP LW LV
SRVVLEOHWRNQRFNGRZQH[SUHVVLRQRIĮ(1D&P51$VLQSXOPRnary epithelial cells and thus reduce 
the number of active ENaC channels on the epithelial cell. 
 
Reduced ENaC channel activity, should lead to improved hydration and mucus clearance in patients 
with CF. Since mucus dehydration and impaired mucociliary clearance results in 
infective/inflammatory sequelae, including airway mucus obstruction and disseminated 
bronchiectasis, recurrent bacterial infections, chronic inflammation, and lung damage/scarring in 

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patients with CF, improved mucus hydration and clearance is expected to prevent further pulmonary 
injury and allow for a reduction in CF induced sequelae. This therapeutic rationale is supported by 
human genetics where CF patients who are deficient in CFTR function (F508del mutations) but also 
harbor an ENaC loss-of-function mutation have milder CF symptoms compared to those with wild 
type ENaC and are reported to live into their 5th or 6th decade. (Agrawal 2017). Patients with normal 
CFTR function but with an ENaC activating mutation have a CF like phenotype (Rauh 2010). 
Additionally, patients homozygous for ENaC loss-of-function mutations have been shown to have 
enhanced mucociliary clearance relative to non-carriers (Kerem 1999). Such genetic target validation 
has inspired development of inhaled small molecule ENaC inhibitors which have been investigated 
in clinical trials. However, systemic absorption via the lung has caused discontinuation of small 
molecule studies secondary to renal uptake of small molecules by the distal tubule leading to dose 
limiting hyperkalemia in some studies (O’Riordan 2014). 
 
The RNAi trigger in ARO-(1D&ZDVGHVLJQHGWRVSHFLILFDOO\WDUJHWRQO\WKHĮ(1D&P51$VL51$
is poorly absorbed by most cell types without an appropriate surface receptor targeting ligand to 
induce endosomal uptake. Thus, uptake by non-pulmonary epithelial cells, such as cells in the renal 
distal tubule or collecting duct is not likely. In contrast to small molecule ENaC inhibitors, localized 
inhaled nebulized delivery of siRNA has shown very minimal systemic uptake with the majority of 
delivered drug remaining in the lung. Additionally, intravenous delivery of ARO-ENaC also does 
not induce significant ENaC gene silencing in the kidney and with both nebulized and intravenous 
delivery, no hyperkalemia has been seen in non-clinical studies (See Investigator’s Brochure). 
 
Combining ENaC Inhibition with CFTR Modulators 
Even in the setting of broadly used CFTR modulators, there remains an unmet medical need in CF 
patients. CF related exacerbation rates, which are important clinical events associated with disease 
progression, remain a significant issue even in patients receiving CFTR modulator therapy 
(Middleton 2019). Patients with high unmet need include those for whom no CFTR modulator 
therapies are available, those who are unresponsive to CFTR modulators due to their underlying 
mutations (approximately 10% of the CF population), those who require frequent hospitalization 
due to CF-related exacerbations, and those who do not tolerate inhaled antibiotics. There is a strong 
rationale for the potential of synergistic effects of ENaC inhibition and CFTR modulators in the 90 
% that respond to elexacaftor/tezacaftor/ivacaftor. The rescue of CFTR by modulators is not perfect 
(~50% at functional level) and based on physiology, inhibition of ENaC is predicted to 
hyperpolarize the cell membrane potential and thus increase the driving force for chloride secretion 
via modulator-rescued mutant CFTR. Therefore, even patients for which CFTR modulator therapy 
is available are expected to have additional benefit from the development of new “add-on” therapies 
(Mall 2019). 
 
ENaC inhibition may act synergistically with CFTR modulators. CFTR can secrete or absorb Cl- 
across epithelial surfaces depending on the driving force that is determined by i) the intra- and 
extracellular Cl- concentrations that are tightly regulated and result in a Nernst potential for Cl- in the 
range of –30 mV in airway epithelial cells, and ii) the membrane potential of the cell that is set by the 
relative conductances of Cl-, Na+ and K+ channels and respective intra- and extracellular 
concentrations of these ions (Boucher 1994; Boucher 1994; Willumsen 1989). It is therefore 
predicted that if ENaC is inactive or not expressed in the same cell, cAMP-mediated stimulation will 
lead to a concomitant activation of apical CFTR and basolateral K+ channels that drives the 
membrane potential more negative than the Nernst potential of Cl-, and thus generate a driving force 
for CFTR-mediated Cl- secretion. However, if ENaC is active in the same cell, this will depolarize 
the membrane potential, reduce the driving force for Cl- secretion, and may evenresult in CFTR-

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mediated Cl- absorption as observed in the sweat duct (Boucher 1994; Boucher 1994; Willumsen 
1991; Willumsen 1989; Greger 1996; Quinton 1983). The implications of these physiological 
findings on the combination of CFTR modulators and ENaC inhibitors in patients with CF are that 
inhibition of hyperactive ENaC in the apical membrane of airway epithelial cells may not only block 
ENaC-mediated Na+/fluid absorption, but will also hyperpolarize the apical cell membrane and thus 
increase the driving force for Cl-/fluid secretion via mutant CFTR channels that have been rescued and 
inserted into the apical plasma membrane in the setting of CFTR modulator use. Whether this results 
in synergistic effects on airway surface hydration, MCC and pulmonary outcomes in patients with 
CF and other muco-obstructive lung diseases needs to be assessed in clinical trials. However, there 
is a plausible scientific rationale for synergistic effect when using CFTR modulators with ENaC 
inhibition. 
 
5.3. 
ARO-ENaC Pre-Clinical Pharmacology Studies 
Further information on the pre-clinical pharmacology studies in monkey, rodent and sheep 
models is provided in the Investigator’s Brochure. 
 
5.4. 
ARO-ENaC Pre-Clinical Pharmacokinetic and Product Metabolism Studies 
PK parameters for ARO-ENaC have been evaluated in multiple species. Results of these studies 
can be found in the Investigator’s Brochure. 
 
5.5. 
ARO-ENaC Pre-Clinical Toxicology Studies 
ARO-ENaC has been clinically well tolerated in rats and in non-human primate toxicology 
studies. Details regarding GLP and non-GLP toxicology results are provided in the 
Investigator’s Brochure. 
 
5.6. 
Rationale for the Study 
AROENAC1001 is a first in human dose-ranging study to assess the safety and tolerability of 
ARO-ENaC in healthy volunteers and in patients with CF. Arrowhead follows general principles 
of EMA and FDA guidance which indicate first-in-human (FIH) studies should initiate in 
healthy volunteers unless the drug is known or suspected to be unavoidably toxic or associated 
with a high degree of toxicity (e.g. chemotherapy or other oncology compounds). This is not the 
case with ARO-ENaC based on GLP toxicology results (See Investigator’s Brochure). 
 
Arrowhead believes valuable scientific information will be gained from the initial NHV 
component of the AROENAC1001 study. For example, healthy volunteers provide valuable 
tolerability and PK information in the absence of disease and can provide information that can be 
used for comparative purposes to patient groups. Additionally, results of a FIH study in CF patients 
may be difficult to interpret for the following reasons: 
 
1. CF patients as part of their underlying disease may have fluctuations in labs (e.g. ALT and 
AST) and pulmonary status. These factors make initial safety data interpretation difficult and 
support initial first in man evaluation in an NHV population with minimal co-morbidities, 
normal lung function and normal laboratory values at baseline. Based on the GLP toxicology 
results, ARO-ENaC should be appropriately safe for healthy volunteers. 
 
2. CF patients are commonly on concomitant medications for the treatment of CF and other co-
morbid conditions. It would be beneficial to initially study ARO-ENaC in a healthy volunteer 
population not confounded by additional medications. 

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For these reasons, the study initiates in healthy volunteers and pending safety evaluation in NHVs, 
also enrolls CF patients. Treatment with ARO-ENaC is expected to reduce pulmonary epithelial 
ENaC channel density via RNAi. The magnitude of the reduction and duration of effect will 
depend on the dose. Since there has not been human clinical exposure to ARO-ENaC, an effective 
therapeutic dose to administer to patients with CF in later stage efficacy studies is unknown. Thus, 
the study plans to dose escalate in NHVs and will also evaluate multiple dose levels in CF patients. 
 
The study begins with single dose cycle administration to healthy volunteers to evaluate ARO-
ENaC for the purpose of understanding safety profile. There are no known serum biomarkers of 
ENaC; thus to gauge pharmacodynamic response in NHVs bronchoscopy with bronchial brushing 
and bronchoalveolar lavage (BAL) is planned to obtain airway epithelial cells (from brushing) and 
airway exosomes (from BAL) for analysis of αENaC expression. Serum electrolytes will be 
monitored carefully with particular attention to potassium levels. 
 
CF patients will require multiple doses of ARO-ENaC to sustain gene target silencing. 
Accordingly, this study uses a multiple-ascending dose (MAD) design to determine the dose 
required to reach and sustain maximal knockdown in pulmonary epithelial ENaC levels, and the 
dose-response relationship in patients with CF. There is no readily measurable serum assay for 
ENaC gene target silencing in humans. However, FEV1 and Lung Clearance Index have been 
used and well validated in multiple CF studies as potential markers of drug efficacy. LCI is time 
consuming in subjects with ppFEV1 < 70%; for feasibility reasons in CF cohorts 2b-4b, LCI will 
only be performed in subjects with ppFEV1 >70% and CF cohort 4b will be restricted to subjects 
with ppFEV1 >70% to allow for LCI assessments of all subjects in that cohort. CF cohort 6 will 
trial a different approach, with LCI assessments in all subjects, even in those with ppFEV1 <70%. 
 
CF cohort 6 is included in the study in order to assess the safety and efficacy of an alternate dosing 
regimen in CF patients. In this cohort, patients will be dosed on Days 1, 15, and 29, as opposed to 
Days 1, 2, 3 and 22, 23, 24 as in other CF cohorts. The respirable delivered dose (RDD, which is the 
amount of drug that reaches the lung, as opposed to the amount of drug loaded in the nebulizer) 
given on Day 1 to subjects in cohort 6 will be equal to or less than the total cumulative RDD given 
over Days 1, 2, and 3 to subjects in CF cohort 4b (which is the cohort receiving the highest dose 
level among CF cohorts 2b, 3b, 4b). The rationale for testing this dosing regimen is that sheep 
pharmacology studies indicate similar efficacy of ARO-ENaC when given via one single, larger dose 
as when given via three smaller daily doses. Additionally, sheep studies indicate a waning of drug 
effect at 3 weeks post-dose, providing the rationale for testing a 2 week dosing interval. 
5.7. 
Risk Assessment for Participants 
• Embryo-Fetal: Limited GLP toxicology studies have been conducted. Accordingly, eligible 
participants enrolled in this study, both male and female (including partners), must agree to 
use two highly effective forms of contraception during the study and for 3 months post-dose, 
or agree to abstinence (acceptable only if this method is in alignment with the normal 
lifestyle of the patient). 
 
• Electrolyte Disturbances: Small molecule inhibitors of ENaC have been associated with mild 
hyperkalemia (O’Riordan 2014). This was due to systemic absorption of the small molecule 
inhibitors with ENaC inhibition in the kidney distal tubule leading to potassium reabsorption. 
ARO-ENaC has not been shown to produce hyperkalemia in various GLP toxicology studies 
when administered via inhaled nebulized solution and even when administered intravenously. 

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Avoidance of renal ENaC inhibition and associated hyperkalemia is facilitated by local 
nebulized delivery and the poor uptake of siRNA molecules by cells lacking the appropriate 
receptor. Hyperkalemia is not expected in this study. However, frequent monitoring, avoidance 
of medications known to cause hyperkalemia, stopping rules for hyperkalemia and a 
hyperkalemia treatment guideline (Section 16.2) are utilized to mitigate risk. 
 
• Pulmonary: GLP animal toxicology studies have not revealed evidence of pulmonary toxicity 
at clinically relevant doses and NOAELs from such studies provide a wide therapeutic index. 
However, as this is the first administration of ARO-ENaC in humans, careful monitoring of 
pulmonary function is prudent. Very frequent measurement and tracking of FEV1 as described 
in the SOA and stopping rules for adverse changes in lung function are intended to mitigate the 
risk of pulmonary toxicity. 
 
• Bronchoscopy: This is a semi-invasive procedure involving sedation, local anesthesia and 
insertion of a bronchoscope into the airways. Following insertion of the bronchoscope, 
bronchoalveolar lavage and bronchial brushings will be performed; notably, no transbronchial 
biopsies will be taken. Bronchial brushings will be taken from the lung periphery under 
fluoroscopic visualization of brush location. Complications of bronchoscopy include sore 
throat, bronchospasm, hypoxemia, laryngospasm or laryngeal injury, fever, and adverse 
reactions to sedation. The most common adverse event is laryngospasm which occurs in 0.6% 
of flexible bronchoscopies (Pue 1995). More severe complications such as pneumothorax and 
pulmonary hemorrhage are rare (0.1 to 0.2% for each) and occur more frequently in the setting 
of transbronchial biopsies, which will not be performed in this study (Pue 1995; Facciolongo 
2009). Patient selection has a significant impact on procedural complications and the risks of 
bronchoscopy in normal healthy volunteers will be lower than in patients with underlying 
respiratory disease. 
5.8. 
Justification for Doses in Humans 
Detailed calculations related to pulmonary deposited dose are provided in the Investigator’s 
Brochure Section 8.2.2. In animals, pulmonary deposited dose (PDD) refers to the amount of 
drug reaching the lung tissue. Assuming a 100% deposition fraction, the equivalent measure in 
humans is respirable delivered dose (RDD). Pharmacologic activity of inhaled ARO-ENaC was 
determined in sheep, where dose dependent increases in mucociliary clearance were observed at 
doses of 0.04 to 0.5 mg of pulmonary deposited dose (PDD) per kg body weight dosed on each of 
days 1, 2, 3. This translates to human respirable delivered doses of approximately 3.0 mg to 30 mg 
in a 60 kg patient (0.05 to 0.5 mg respirable delivered dose per kg of body weight). 
Similar pharmacologic activity was seen in sheep when a single, larger dose of 1.7 mg PDD per 
kg was given on day 1, which translates to a human RDD of 102 mg in a 60 kg person. 
 
Therefore, all dose levels evaluated in the AROENAC1001 study are expected to result in dose 
dependent pulmonary ENaC channel suppression and increasing pharmacologic activity using the 
proposed dosing schedule. Sheep pharmacology studies show efficacious acceleration of 
mucociliary clearance at 2 weeks post-dose, which wanes at 3 weeks post-dose and returns to 
baseline by 4 weeks post-dose. Thus, for patient cohorts receiving multiple cycles of ARO-ENaC, 
dosing frequencies of either 2 weeks or 3 weeks will be tested in this study. 
In assessing the human risk associated with inhalation of ARO-ENaC, consideration must be given to 
both the potential to elicit systemic toxicity as well as pulmonary toxicity. The initial clinical 
evaluation of ARO-ENaC in the AROENAC1001 study evaluates two different dosing regimens: a 3-
day dosing cycle (Days 1, 2, and 3) in healthy volunteer cohorts 1-5 which is repeated after a 3-week 

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interval (Days 22, 23, and 24) in CF cohorts 2b-4b; as well as one, single dose repeated at 2-week 
intervals (Days 1, 15, and 29) in CF cohort 6. Safety margin considerations are provided for the 
highest dose regimen (cohort 6) utilizing exposure (AUC) and NOAEL data generated from the 24-
day toxicity studies where ARO-ENaC was dosed on Days 1, 2, 3, 22, 23, and 24. While these dosing 
schedules differ, the total number of doses given in clinical Cohort 6 is fewer and at less frequent 
intervals than the doses given in the nonclinical toxicology studies. 
The maximum human dose in this initial clinical study is 1.5 mg respirable delivered dose (RDD)/kg 
body weight given as a daily dose on Days 1, 15, and 29, to subjects in cohort 6. Based on a 60 kg 
human, the total human therapeutic dose of ARO-ENaC would be 90 mg RDD. Assuming a standard 
human lung weight of 1 kg or 1000 g (Tepper 2016) results in a lung dose of 0.09 mg RDD/g lung 
weight. The 0.09 mg RDD/g lung weight value can then be compared to values from the animal study 
to derive safety margins for lung effects. In rats, the NOAEL was considered to be 10.1 mg 
pulmonary deposited dose (PDD)/kg body weight and based on an average terminal body weight of 
0.323 kg, the total administered dose of ARO-ENaC was 3.26 mg PDD. Assuming a standard rat lung 
weight of 1.5 g (Tepper 2016) results in an ARO-ENaC dose of 2.17 mg PDD/g lung weight. In 
monkeys, the NOAEL was considered to be 9.9 mg PDD/kg body weight and based on an average 
terminal body weight of 2.3 kg, the total administered dose of ARO-ENaC was 22.77 mg PDD. 
Assuming a standard monkey lung weight of 22 g (Tepper 2016) results in an ARO-ENaC dose of 
1.04 mg PDD/g lung weight. Comparing the anticipated maximum human dose, 0.09 mg RDD/g lung 
weight, to the NOAEL dose in rats, 2.17 mg PDD/g lung weight, and the NOAEL dose in monkeys, 
1.04 mg PDD/g lung weight, yields safety margins for lung effects of approximately 24X in rats and 
12X in monkeys (Table 1). These safety margins for lung effects exceed those considered adequate 
by the FDA, which are 10X in rats and 5X in monkeys (Tepper 2016). 
A more conservative estimate of the human nominal inhaled dose than RDD is the delivered dose 
(DD). DD is the amount of drug aerosolized by the nebulizer, while RDD is the amount of aerosolized 
drug contained in droplets of a size suitable for penetration into the lungs. The maximum cohort 6 
dose of 1.5 mg RDD/kg body weight results in 0.09 mg RDD/g lung weight and 0.164 mg DD/g lung 
weight. Comparison of the maximum human delivered dose, 0.164 mg DD/g lung weight, to the PDD 
at the NOAEL in rats and monkeys, results in the more conservative safety margin estimates for lung 
effects of 13X in rats and 6X in monkeys (Table 1). This more conservative estimate of safety 
margins for lung effects still produces margins considered adequate by the FDA (Tepper 2016). 
Safety margins for systemic effects were calculated utilizing interim clinical PK data from the 
ongoing AROENAC1001 study, by comparing the estimated plasma AUC inf following the highest 
planned human dose of approximately 90 mg RDD (3730 h*ng/mL) with the plasma AUC last at the 
NOAEL in rats (61900 h*ng/mL), and at the NOAEL in female monkeys (38900 h*ng/mL) as well as 
male monkeys (58400 h*ng/mL). This results in a safety margin for systemic effects of at least 16.6X 
in rats (61900 h*ng/mL ÷ 3730 h*ng/mL), 10.4X in female monkeys (38900 h*ng/mL ÷ 3730 
h*ng/mL), and 15.7X in male monkeys (58400 h*ng/mL ÷ 3730 h*ng/mL) (Table 2). These safety 
margins for systemic effects to support the proposed clinical dose when calculated by AUC 
comparisons exceed those considered adequate by the FDA, which are 1X in both rats and monkeys 
(Tepper 2016). 
Collectively, the results of the in vitro and in vivo nonclinical safety studies, as well as the 
estimated safety margins for both systemic and lung effects, support the continued clinical 
development of ARO-ENaC at the dose levels planned in this study.  
 
 
 

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Table 1. Safety margins for lung effects using the maximum planned clinical dose of 
approximately 90 mg respirable delivered dose (RDD) in cohort 6 
 
Human 
RDDa 
(mg/g) 
Human 
DDa 
(mg/g) 
Rat PDD at 
NOAELb 
(mg/g) 
Rat Safety 
Margin 
using RDD 
Rat Safety 
Margin 
using DD 
Monkey 
PDD at 
NOAELb 
(mg/g) 
Monkey 
Safety 
Margin 
using RDD 
Monkey 
Safety 
Margin 
using DD 
0.09 
0.164 
2.17 
24 
13 
1.04 
12 
6 
a Clinical doses given on Days 1, 15, 29. RDD and DD reflect average daily dose. 
b GLP toxicology study doses given on Days 1, 2, 3, 22, 23, 24. PDD reflects average daily dose. 
 
Table 2. Safety margins for systemic effects using the maximum planned clinical dose of 
approximately 90 mg respirable delivered dose (RDD) in cohort 6 
 
Human 
RDDa 
(mg) 
Estimated 
Human 
AUC inf 
(h*ng/mL) 
Rat 
AUC last  at 
NOAELb  
(h*ng/mL) 
Rat 
Safety 
Margin 
Male 
Monkey 
AUC last  at 
NOAELb 
(h*ng/mL) 
Male 
Monkey 
Safety 
Margin 
Female 
Monkey 
AUC last  at 
NOAELb 
(h*ng/mL) 
Female 
Monkey 
Safety 
Margin 
92.1 
3730 
61,900 
16.6 
58,400 
15.7 
38,900 
10.4 
a Clinical doses given on Days 1, 15, 29.  
b GLP toxicology study doses given on Days 1, 2, 3, 22, 23, 24.  
 
It is important to note that while weight-based safety margins are calculated based on animal 
PDD compared to human RDD or DD, the RDD and DD are not the dose loaded into the 
nebulizer device. The nebulizer loaded dose required to achieve a certain RDD depends on the 
efficiency of the nebulizer. A table converting RDD into actual nebulizer loading dose is 
provided (Table 3). 
 
 

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3. Pharmacokinetics of ARO-ENaC in NHVs and in CF patients 
6.3. 
Exploratory Endpoints 
1. Changes from pre-dose baseline in FEV1 in CF patients 
2. Changes from pre-dose baseline in lung clearance index (LCI) in CF patients 
3. Changes from pre-dose baseline in the revised cystic fibrosis questionnaire (CFQ-R) in 
CF patients 
4. Rate of pulmonary exacerbations in CF patients receiving ARO-ENaC versus PBO 
5. Changes from pre-dose baseline in body mass index (BMI) in CF patients 
6. Plasma metabolite identification in NHVs (reported in a separate report outside of this 
study) 
7. Determination of urinary excretion and metabolite identification in NHVs (reported in a 
separate report outside of this study) 
8. Changes from pre-dose baseline to Day 18 in expression of ENaC using bronchoscopic 
brush biopsy samples in NHVs 
9. Changes from pre-dose baseline to Day 18 in expression of ENaC using bronchoalveolar 
lavage (BAL) samples in NHVs 
10. Changes from pre-dose baseline to Day 18 in cytokine levels as well as cell count and 
differential in BAL fluid in NHVs 
 
7. 
STUDY PLAN 
7.1. 
Study Design 
Normal Healthy Volunteers: 
While ARO-ENaC is intended for use in CF patients, these patients suffer from frequent disease 
exacerbations and are frequently on multiple concomitant medications. For this reason, this study 
initially evaluates each dose level in a healthy volunteer population to generate a baseline 
understanding of safety in a population with normal physiology and without the confounding factor 
of concomitant medication use. 
For NHVs, 4 cohorts of 6 eligible subjects (4 active: 2 PBO) will be evaluated at each dose level 
starting with Cohort 1. Cohort 5 will include 12 eligible patients (8 active: 4 placebo) who will be 
treated with a dose equal to or less than that given to cohort 4, with the purpose of collecting 
bronchoscopic samples to evaluate for αENaC mRNA knockdown. Participants who have signed 
an IRB/EC approved informed consent form and have met all of the protocol eligibility criteria 
during screening, will be randomized to receive ARO-ENaC or PBO. NHV cohorts will receive a 
single cycle of three doses all at a fixed dose level administered daily on Days 1, 2, 3. 
 
NHV cohorts 1-4 will begin with administration of ARO-ENaC or PBO to two sentinel 
participants (one ARO-ENaC, one PBO). Following the Day 4 evaluation in these participants, if 
there are no significant safety concerns based on PI’s judgement, the remaining participants in the 
cohort will be dosed. Cohort 5 will not utilize sentinel participants as the dose evaluated in cohort 5 will 
be equal to or lower than doses used in cohorts 1-4. Dosing of participants will be staggered by at 
least 30 minutes such that no two participants will be dosed simultaneously. Blood samples will be 
drawn pre-dose on Day 1 for baseline measurements. 

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Based on observations for all NHV subjects in a cohort through Day 21, and experience from 
any prior cohorts (i.e. all cumulative available safety data), the DSC will meet to vote on the 
following (See Fig. 1): 
1. 
Dose escalation to next NHV cohort 
2. 
Initiation of CF cohort (Cohorts 2b, 3b, 4b) when applicable per Figure 1. 
Escalation to the next highest dose level in NHVs will proceed in cohorts of 6 until the highest 
planned dose level is completed, or the trial is halted prematurely by the PI, DSC or Sponsor due 
to safety or other concerns. 
Following an affirmative vote from the DSC meeting held during NHV cohort 4 allowing the 
opening of CF Cohort 4b, NHV cohort 5 may be subsequently opened for accrual. The primary 
purpose of cohort 5 will be to assess the effect of ARO-ENaC on αENaC mRNA expression, with 
samples obtained via bronchoscopy. The dose in cohort 5 will be equivalent to or less than the dose 
utilized in cohort 4. Based on available safety data reviewed during prior DSC meetings, the 
Sponsor or DSC may adjust the dose in cohort 5 downward. 
The DSC will consist of at least one study Investigator, Sponsor Medical Monitor, Sponsor 
pharmacovigilance lead, and an independent physician experienced in pulmonary drug 
development and/or early stage clinical trials. 
Cystic Fibrosis Patients: 
Cohorts 2b, 3b, 4b will enroll eligible CF patients who have signed an IRB/EC approved informed 
consent form to receive two cycles of ARO-ENaC or PBO administered daily on Days 1, 2 and 3, 
then again on Days 22, 23 and 24. Screening for the CF cohorts can begin once Cohort 2 dosing 
has commenced but dose administration may not proceed until after the DSC has opened the 
designated CF patient cohort. CF patient cohorts 2b, 3b, and 4b will be opened for accrual once 
the corresponding NHV cohort receiving the same dose level has reached Day 21 and based on 
DSC vote that it is safe to proceed. CF patient cohorts 2b, 3b, and 4b will enroll in sequence with 
2b enrolling first, followed by 3b and then Cohort 4b. 
Once all subjects in CF cohort 4b have completed the Day 29 study visit, the DSC will meet to 
review all cumulative safety data to date and to vote on the initiation of CF cohort 6. Following an 
affirmative vote from this DSC meeting, CF cohort 6 may be opened for accrual. The purpose of 
cohort 6 is to assess the safety and efficacy of an alternate dosing regimen. In CF cohort 6, the 3- day 
dosing cycle used in cohort 4b is compressed to a single dose, which is given at 2 week intervals, 
such that subjects will be dosed on Days 1, 15, and 29. The dose given on each dosing day to a 
subject in CF cohort 6 (in respirable delivered dose [RDD] terms, which represents the amount of 
drug that reaches the lung, as opposed to the amount of drug loaded into the nebulizer) will be ≤ 3x 
the dose given on each dosing day to a subject in CF cohort 4b. Thus, the dose (in RDD terms) given 
on Day 1 to a subject in cohort 6 will be ≤ the total cumulative dosage given over Days 1, 2, and 3 to 
a subject in cohort 4b. Of note, the RDD does not scale identically to the nebulizer loaded dose (i.e. 
tripling the RDD does not necessarily result in tripling the nebulizer loaded dose). 
Blinding (where applicable) will be preserved to the extent possible. However, treatment un-
blinding or un-blinding of an individual participant may occur, at the discretion of the PI or 
Medical Monitor, where deemed necessary for treatment of an AE or for a decision to be made 
regarding trial continuation. After all subjects in a cohort (except cohort 6) have completed an 
End-of-Study visit, Sponsor may be unblinded to that cohort. PI and study participants will 
remain blinded.  

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Primary analysis is planned once both all subjects in cohort 6 have completed the Day 43 visit 
and all subjects from other cohorts have completed EOS. PIs and study participants will remain 
blinded through EOS. Sponsor will be unblinded to analyze both safety and efficacy endpoints 
for all NHV and CF cohorts. Final Analysis is planned when all subjects ended study and 
database is locked. Safety and efficacy results will be updated based on complete database in 
final analysis. 
 
Table 4: Cohort Summary 
 
Cohort 
Population 
Blinding 
# Subjects 
Dosing Schedule 
1 
NHVs 
Double-blind 
6 (4 active: 2 PBO) 
20 mg Day 1, 2, 3 
2 
NHVs 
Double-blind 
6 (4 active: 2 PBO) 
40 mg Day 1, 2, 3 
3 
NHVs 
Double-blind 
6 (4 active: 2 PBO) 
65 mg Day 1, 2, 3 
4 
NHVs 
Double-blind 
6 (4 active: 2 PBO) 
≤ 180 mg Day 1, 2, 3 
5 
NHVs 
Double-blind 
12 (8 active: 4 PBO) ≤ 180 mg Day 1, 2, 3 
2b 
CF Patients 
Double-blind 
Up to 6 (4 active: 
2 PBO) 
≤ 40 mg dosed on Day 1, 2, 
3; ≤ 40 mg dosed on Day 
22, 23, 24 
3b 
CF Patients 
Double-blind 
Up to 6 (4 active: 
2 PBO) 
≤ 65 mg dosed on Day 1, 2, 
3; ≤ 65 mg dosed on Day 
22, 23, 24 
4b 
CF Patients (ppFEV1 > 70%) 
Double-blind 
Up to 12 (9 active: 3 
PBO) 
≤ 180 mg dosed on Day 1, 
2, 3; ≤ 180 mg dosed on 
Day 22, 23, 24 
6 
CF Patients 
Double-blind 
Up to 24 (18 active: 
6 PBO) 
≤ 490 mg dosed on Day 1; ≤ 
490 mg dosed on Day 15; ≤ 
490 mg dosed on Day 29 
 
The dose escalation schedule is outlined in Figure 1. 
 
 

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Figure 1: Dose Escalation Schedule 
 
 
 
 
 
* Cohorts 1-4 each use 2 sentinel subjects dosed before the rest of the cohort. Where specified, dose represents 
the highest dose that may be used in the cohort. The DSC or Sponsor may adjust the dose downward if 
indicated based on available safety data. 
ǂ specified dose given once on Day 1, Day 2 and Day 3 
** Cohorts 2b, 3b, 4b, and 6 enroll in sequence per Figure 1 and after associated DSC approval. 
7.2. 
Rationale for Study Design 
While ARO-ENaC is intended for use in CF patients, these patients suffer from frequent disease 
exacerbations and are frequently on multiple concomitant medications. For this reason, this study 
initially evaluates each dose level in a healthy volunteer population to generate a baseline 
understanding of safety in a population with normal physiology and without the confounding factor of 
concomitant medication use. 
This FIH study plans to investigate ARO-ENaC in normal healthy volunteers to evaluate the 
drug’s safety and tolerability. The study initiates in healthy volunteers because the risk is 
considered low based on GLP animal toxicity testing. It is expected that treatment of CF with 
ARO-ENaC will require multiple doses; thus, this study in healthy volunteers transitions from a 
single cycle of three doses to two cycles of three doses each (on Days 1, 2, 3 and Days 22, 23, 
24) in patients with CF if safety data is acceptable to DSC. 
 
Cohort 5 is included in the study to evaluate for changes in αENaC expression following ARO- ENaC 

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dosing in NHVs, utilizing samples obtained via bronchoscopy, as there is no known serum marker of 
pharmacodynamic effect for ARO-ENaC. 
 
CF cohort 6 is included in the study to compare the safety and efficacy of compressing the dosing 
regimen of ARO-ENaC from daily dosing over three days to one single, larger dose given every 
two weeks. The rationale for testing this dosing regimen is that sheep pharmacology studies 
indicate similar efficacy of ARO-ENaC when given via one single, larger dose as when given via 
three smaller daily doses. Additionally, sheep studies indicate a waning of drug effect at 3 weeks 
post-dose, providing the rationale for testing a 2 week dosing interval. 
 
All cohorts in the study are double-blind to limit the occurrence of conscious and unconscious bias 
in trial conduct and interpretation. Blinding will be achieved using a PBO (0.9% normal saline). 
Inclusion of participants receiving PBO will reduce bias in the assessment of drug safety and 
tolerability. The patient cohorts are proposed to understand multiple dose safety, 
pharmacodynamics and pharmacokinetics which should assist with dose selection in later stage 
clinical studies. 
 
LCI data will be collected for all subjects in cohorts 4b and 6 and for a subset of patients in 
cohorts 2b and 3b (the subset of patients with ppFEV1 >70%). LCI collection is feasible but 
time consuming in those with more severe lung disease; for this reason, CF cohorts 2b, 3b 
and 4b only assess LCI in those with ppFEV1 >70% and CF cohort 4b only enrolls patients 
with ppFEV1 > 70%. CF cohort 6 trials a different approach, and will collect LCI 
measurements on all subjects in the cohort, even those with ppFEV1 < 70%. 
 
7.3. 
DSC and Criteria for Dose-escalation and Dose Limiting Toxicities 
Escalation to the next cohort will proceed according to the study design until the highest planned 
dose cohort is completed, unless the trial is stopped early by the DSC, PI or Sponsor. Dose 
escalation will require approval by the DSC based on evaluation of all available safety and, when 
available, pharmacodynamic data through at least Day 21 of the most advanced NHV cohort. The 
DSC meeting held during CF cohort 4b will review all cumulative safety data to date, through the 
Day 29 visit of CF cohort 4b. 
7.4. 
Stopping Rules & Data Safety Committee 
A decision to stop the trial early or discontinue drug in an individual subject, group of subjects or 
to halt enrollment temporarily or permanently may be indicated based on any of the following: 
1. A single Serious Adverse Event (SAE, defined in Section 11.1) considered at least 
possibly related to study drug 
2. Two cases of a drop from baseline FEV1 (which must be confirmed on repeat within 48 
hours) in healthy volunteer cohorts of ≥ 20% (absolute decline in % of predicted) 
considered to be at least possibly related to study drug by study investigator 
3. One case of a drop from baseline FEV1 (which must be confirmed on repeat within 48 hours) 
in cystic fibrosis cohorts of ≥ 20% (absolute decline in % of predicted) considered to be 
probably related to study drug by study investigator. 
4. A post-dose increase in serum potassium to > 5.7 milliequivalents/Liter which must be from 
a non-hemolyzed sample and confirmed by repeat blood draw within 48 hours of initial 
results. 
 

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If any such events occur, within 5 days of Sponsor being notified of the event, the DSC will 
meet to review the event and determine any necessary actions as detailed below. Further 
dosing of the subject who triggered the stopping rule will be paused until such DSC review 
occurs. 
 
Central labs will be utilized. However local labs may be utilized as necessary (including for 
Screening) if needed by the investigator or for emergent situations, including time critical 
analytes such as serum potassium and repeat clinical chemistries. 
 
The Sponsor or PI can discontinue any subject at any time with or without DSC consultation. If 
such events (as described above) occur and the subject is not discontinued from the study the 
reason for not discontinuing the subject will be included in DSC meeting minutes. Including, but 
not limited to the events listed above, the DSC may pause the study to additional dosing or dose 
escalation to provide time to evaluate safety data and recommend the action to be taken, which 
may include, but is not limited to one of the following: 
 
• 
Discontinuation of a subject or group of subjects from the study 
• 
The study is stopped immediately with no further dosing 
• 
The study will continue until the current cohort is completed 
• 
The study will continue, but the next dose escalation will be to a level midway 
between the current level and the next planned level 
• 
The study will continue as planned 
 
The DSC will consist of at least the Sponsor Medical Monitor, Sponsor pharmacovigilance lead, a 
study Investigator and an independent physician experienced in Phase 1 clinical trials. 
 
7.5. 
 Primary Analysis and Final Analysis 
Primary analysis is planned once both all subjects in cohort 6 have completed the Day 43 
study visit and all subjects from other cohorts have completed EOS. PIs and study participants 
will remain blinded through EOS. Sponsor will be unblinded to analyze both safety and 
efficacy endpoints for all NHV and CF cohorts. Final Analysis is planned when all subjects 
have ended the study and the database is locked. Safety and efficacy results will be updated 
based on complete database in final analysis.  
7.6. 
Duration of the Study 
For each NHV subject the approximate duration of the study clinic visits is a maximum of 8 
weeks from the beginning of the Screening period to the Day 29 End-of-Study (EOS) 
examination. 
For each CF patient, the duration of the study is approximately 20 weeks from the beginning 
of the Screening period to the Day 113 EOS examination. 
 
8. 
PATIENT SELECTION 
8.1. 
Number of Patients 
Approximately 36 NHVs and up to 56 CF patients (including up to 2 extra patients per cohort in 
Screening and not including potential replacements) may be enrolled in the study. 
 
 

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8.2. 
Inclusion Criteria 
Applicable to NHV and CF Cohorts 
To be eligible for participation, NHVs and CF patients must meet all the following inclusion 
criteria: 
1. Male or non-pregnant, non-lactating female volunteers 18-55 years of age, inclusive at 
time of Screening 
2. Normal ppFEV1 (>80%) at Screening in NHVs only 
3. Able and willing to provide written informed consent prior to the performance of any 
study specific procedures 
4. Participants with a BMI between 18.0 and 35.0 kg/m2, inclusive, at Screening 
5. A 12-lead ECG at Screening with no abnormalities that may compromise participant’s 
safety in this study 
6. Non-smoker (smoker is defined as smoking cigarettes daily for at least the past 12 
months) with current non-smoking status confirmed by urine cotinine at Screening AND 
any previous smoking history prior to 12 months must be < 15 pack years. Patients may 
be on nicotine replacement (patch or gum). e-cigarettes (vapor) is not permitted. A 
positive urine cotinine result due to nicotine replacement is acceptable for enrollment at 
the discretion of the PI.  
7. Participants of childbearing potential must agree to use highly-effective contraception 
during the study and for at least 12 weeks following the end of the study or last dose of 
study drug, whichever is later. Males must not donate sperm during the study and for at 
least 12 weeks following the end of the study or last dose of study drug, whichever is 
later. (See Section 10.6 for details regarding highly-effective contraception). 
8. Participants who are willing and able to comply with all study assessments and adhere to 
the protocol schedule 
9. No abnormal finding of clinical relevance at the Screening evaluation other than CF for 
CF patients 
10. No planned significant dietary changes during the study period. 
Additional Inclusion Criteria for CF Patients 
To be eligible for participation, CF patients must meet all the following inclusion criteria: 
1. All other treatments for CF (including CFTR modulators/correctors) have been stable for 
at least two months (meaning no new medications or changes in dose) prior to first dose 
and patient is willing to continue this treatment regimen without change for study duration. 
2. Confirmed diagnosis of CF based on source verifiable medical record 
3. Percent predicted FEV1 of ≥ 40 to ≤ 90% adjusted for age, sex, and height according to 
NHANES III at the Screening Visit. For Cohort 4b patients must have ppFEV1 > 70%. 
4. Participants with a BMI between 18.0 and 35.0 kg/m2, inclusive, at Screening. 
Participants with BMI between 15-18 kg/m2 or between 35-40 kg/m2 may be enrolled at 
the PI’s discretion in consultation with Sponsor depending on co-morbidities. 
 
 

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8.3. 
Exclusion Criteria 
Applicable to NHV and CF Cohorts unless otherwise specified 
 
A potential NHV and CF participant will be excluded from the study if any of the following criteria 
apply: 
1. Acute lower respiratory infection within 30 days of Screening (NHVs only) 
2. Any history of anaphylaxis  
3. Human immunodeficiency virus infection, as shown by the presence of anti-HIV 
antibody (sero-positive) 
4. Seropositive for HBV or HCV (positive for anti-HCV antibody must be confirmed with 
positive HCV-RNA test for exclusion) 
5. Uncontrolled hypertension (BP > 150/100 mmHg at Screening) 
6. A history of torsades de pointes, ventricular rhythm disturbances (e.g., ventricular 
tachycardia or fibrillation), pathologic sinus bradycardia (<50 bpm with symptoms), 
heart block (excluding first-degree block, being PR interval prolongation only), 
congenital long QT syndrome or new ST segment elevation or depression or new Q 
wave on ECG. Participants with a history of atrial arrhythmias should be discussed with 
the Medical Monitor 
7. A clinically significant history of hyperkalemia or hyperkalemia at Screening 
8. A family history of congenital long QT syndrome or unexplained sudden cardiac death 
9. Medications known to prolong the QTc interval (NHVs only, not applicable to CF 
patients) 
10. Use of prescription diuretics (including amiloride, spironolactone, other potassium 
sparing diuretics), ACE inhibitors, angiotensin receptor blockers, trimethoprim, 
potassium supplements, digoxin, cyclosporine, or tacrolimus. CF patients may be 
eligible after 5-half-life washout period for applicable medication. 
11. Symptomatic heart failure (per NYHA guidelines), unstable angina, myocardial 
infarction, severe cardiovascular disease (ejection fraction < 20%, transient ischemic 
attack (TIA) or cerebrovascular accident (CVA) within 6 months prior to study entry) 
12. History of malignancy within the last 2 years except for adequately treated basal cell 
carcinoma, squamous cell skin cancer, superficial bladder tumors, or in situ cervical 
cancer. Participants with other curatively treated malignancies who have no evidence of 
metastatic disease and >2-year disease-free interval may be entered following approval 
by the Medical Monitor 
13. History of major surgery within 3 months of Screening 
 
14. Unwilling to limit alcohol consumption to within moderate limits for the duration of the 
study, as follows: not more than 14 units per week for women and 21 units per week for 
men (1 Unit = 150 mL of wine, 360 mL of beer, or 45 mL of 40% alcohol) 
15. Use of illicit drugs (such as cocaine, phencyclidine [PCP]) within 1 year prior to the 
Screening visit or positive urine drug screen at Screening (a urine drug screen deemed 

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positive due to prescription medications or for benzodiazepines, opioids or marijuana is 
acceptable and inclusion is at the discretion of the PI) 
16. Use of an investigational agent or device within 30 days prior to first dose or current 
participation in an investigational study 
17. Blood donation (500 mL) within 7 days prior to first dose. Donation or loss of whole 
blood (excluding the volume of blood that will be drawn during the Screening 
procedures of this study) prior to administration of the study treatment as follows: 50 mL 
to 499 mL of whole blood within 30 days, or more than 499 mL of whole blood within 
56 days prior to study treatment administration 
18. Any concomitant medical or psychiatric condition or social situation that would make it 
difficult to comply with protocol requirements or put the participant at additional safety 
risk 
19. Participants who are unable to return for all scheduled study visits 
20. For NHV cohorts only, ALT or AST > ULN at Screening 
21. Serum sodium < LLN or serum potassium > ULN at Screening 
 
22. eGFR of < 60 mL/min/m2, at Screening 
23. Platelet count < LLN at Screening (NHVs only) 
Additional Exclusion Criteria for CF Patients 
A potential participant will be excluded from the study if any of the following criteria apply: 
1. CF exacerbation within 30 days of first dose 
2. History of solid organ transplant 
3. ALT or AST > 2.5 X ULN at Screening 
4. Platelet count < 100,000 at Screening 
5. Diagnosis of hepatic cirrhosis based on medical history and documented in medical 
record or other source document. 
Notes:  
• Sponsor Medical Monitor has the option to exclude the enrollment of a participant if, based 
upon the participant’s medical history or Screening results, it is felt that a participant’s 
safety may be at risk and/or if the safety data may confound or conflict with the study 
results. 
• All spirometry tests used as inclusion criteria and all laboratory tests used as exclusion 
criteria may be repeated once during Screening, with the repeat value used for 
inclusion/exclusion purposes. 
 
8.4. 
Participant Withdrawal Criteria 
Participants will be advised that they are free to withdraw from the study at any time for any 
reason or, if necessary, the PI, or medically trained designee, may withdraw a participant from 
the study, per the following criteria, to protect the participant's health: 
• the need to take medication which may interfere with study measurements 
• intolerable/unacceptable AEs 
• major violation of or deviation from study protocol procedures 

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• non-compliance of participant with protocol 
• participant unwilling to proceed and/or consent is withdrawn 
• withdrawal of the participant from the study if, in the PI’s judgement, it is in the 
participant’s best interest 
• confirmed pregnancy (Note: within 24 hours of awareness of the pregnancy the PI must 
notify the Sponsor [see Section 11].) 
 
The reasons for withdrawal will be recorded on the case report form (CRF) and included in the 
final clinical study report, along with any AEs and any necessary medical treatment. 
 
If a participant is withdrawn from the study due to significant AE or SAE, the PI, or medically 
trained designee, will evaluate the urgency of the event. If the situation warrants, the PI, or 
medically trained designee, will take appropriate diagnostic and therapeutic measures. If the 
situation is not an immediate emergency, the PI, or medically trained designee, at the clinical 
study facility will attempt to contact the Arrowhead Pharmaceuticals, Inc. Medical Monitor or 
medically qualified designee for consultation. No medical help, diagnosis, or advice will be 
withheld from the participant due to an inability to contact the Medical Monitor. The participant 
will be encouraged to remain available for follow-up medical monitoring. The Sponsor will be 
notified as soon as possible of any participant withdrawals. 
 
Participants who are withdrawn or discontinue prior to EOS visit for reasons other than an 
adverse event, may be replaced at Sponsor discretion. 
 
8.5. 
Restrictions and Concomitant Medications 
• Confinement & Study visits: For NHV cohorts, clinical facility confinement will be 
approximately 4 days for single dose administration (Day -1 through Day 4 assessments 
in cohorts 1-4 and Day 0 through Day 4 in cohort 5). Subjects will be admitted to the 
facility on Day -1 (or Day 0 in cohort 5) and will undergo assessments at the facility on 
Days 1, 2, 3 and 4 prior to discharge. After Day 4 assessments NHV participants can be 
discharged and will return to the clinical facility starting on Day 5 for out-patient visits 
per the Schedule of Assessments (SOA). For CF patients, clinical facility confinement 
will be approximately 6 hours on dosing days unless additional monitoring at Principal 
Investigator (PI) discretion is needed for safety reasons. Patients will return to the clinical 
facility for outpatient visits. There is no planned overnight confinement for CF patients. 
• Fasting: On the day of dosing or on other days with blood draws, participants will have 
fasted from food for at least 4 hours prior to study treatment administration or blood draw 
unless otherwise specified or as otherwise required by study procedures. Fasting from food 
and drink will be required beginning at midnight on the night prior to a scheduled 
bronchoscopy, or as otherwise required by study procedures. 
 
• Recreational Drugs & Alcohol: Participants will be instructed to abstain from 
consuming alcohol for at least 48 hours prior to admission, and while confined to the 
clinical facility. In addition, participants will be instructed to refrain from use of alcohol 
above these limits: >14 units per week for women or  >21 units per week for men (1 Unit 
= 150 mL of wine, 360 mL of beer, or 45 mL of 40% alcohol) for the study duration. 
Participants must abstain from use of recreational drugs throughout the study. 
 
• Concomitant Medications: NHVs and CF patients may not use prescription diuretics 

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(including amiloride, spironolactone, other potassium sparing diuretics), ACE 
inhibitors, angiotensin receptor blockers, trimethoprim, potassium supplements, 
digoxin, cyclosporine, or tacrolimus. Use of other concomitant medications may be 
approved by Sponsor Medical Monitor and PI. Patients will be instructed to inform the 
PI of the details (indication, dose and dates of administration) if they do take any 
medication, and these details will be recorded in the CRF. Medication wash-out to 
achieve study eligibility at screen constitutes a protocol procedure and will be preceded 
by informed consent. In CF patients and in NHV cohorts, protein powders, multi-
vitamins (as long as they contain less than 40 mEq potassium taken per day) and fish 
oil are acceptable. Other supplements should be approved by the Medical Monitor. 
9. 
INVESTIGATIONAL PRODUCT 
9.1. 
Description, Identification and Dosage 
Arrowhead Pharmaceuticals, Inc. is responsible for the supply of active drug supplies together 
with detailed instructions (in a pharmacy manual as well as a study procedure manual) describing 
preparation and administration of ARO-ENaC Inhalation. The PBO (0.9% normal saline) will be 
supplied by the clinical site.  
Accordingly, ARO-ENaC Inhalation is provided as a sterile solution containing the API, an 
RNAi trigger molecule conjugated to a targeting moiety for the epithelial integrin αvβ6 (ADS- 
003), ready for inhalation by nebulization. 
The PBO will be nebulized 0.9% normal saline. 
Doses Administered per Dose Level: 
Each single dose of either active drug (ARO-ENaC) or PBO (normal saline 0.9%), will be 
administered by inhaled nebulized solution. ARO-ENaC Inhalation is manufactured by 
dissolution of the lyophilized API into an aqueous normal saline solution which is then aseptically 
filled into glass vials. The resulting solution, ARO-ENaC Inhalation, is administered to the patient 
by inhaled nebulized solution. 
There will be no dose escalation within a cohort (i.e., the same drug dose will be administered to 
each participant within a cohort). The randomization schedule for NHVs and CF patients where 
applicable will be provided to each clinical site and will be maintained along with any other 
materials that could jeopardize the blind in a secured area of the pharmacy. 
 
 
 

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member at the clinical sites. The time of preparation for active drug must be documented and 
tracked to demonstrate administration within prepared drug stability boundaries. Please refer to 
the Pharmacy Manual for more detailed instructions. 
 
The investigational product vials will be labelled per Good Manufacturing Practice 
(cGMP)/Good Clinical Practice (cGCP). 
 
Study drug supplies will be stored at clinical sites securely under the appropriate conditions as 
noted in the Pharmacy Manual. 
9.2. 
Study Drug Handling 
The Sponsor will provide the PI with a sufficient quantity of clinical drug supplies. A Pharmacy 
Manual will be prepared to define the procedures for ordering, storage, and dispensing. Procedures 
for study drug administration are included in the Study Procedure Manual. 
 
The PI must ensure that deliveries of investigational product from the Sponsor are correctly 
received by a responsible person, that all receipts of drug shipments are recorded on the 
appropriate Drug Accountability forms prepared by the pharmacy at the clinical site and that the 
products are stored in a secure area under recommended storage conditions. It is also the 
responsibility of the PI to ensure that the integrity of packaged study product not be jeopardized 
prior to dispensing. 
 
Only participants enrolled in the study may receive study drug, in accordance with all applicable 
regulatory requirements. Only authorized and trained site staff may dispense or administer study 
drug. The study drug must be stored in a secure area with access limited to the PI and authorized 
staff and under the physical conditions that are consistent with the specific requirements stated in the 
Pharmacy Manual. 
 
ARO-ENaC will be supplied by Arrowhead Pharmaceuticals, Inc. and labelled with the drug 
name, batch number, lot number, expiration date (as applicable), and storage conditions. 
Individual doses will be dispensed by clinical trial site staff members on the day of dosing and 
recorded in the drug accountability records. 
 
Procedures delineated in the Pharmacy Manual will be followed for the receipt, handling and 
accountability of the study drug. 
 
9.3. 
Accountability of Study Supplies 
All study related material supplied is only for use in this clinical trial and should not be used 
for any other purpose. The PI is responsible for the investigational product accountability, 
reconciliation and record maintenance at the investigational site. In accordance with all 
applicable regulatory requirements, the PI or designated site staff must maintain investigational 
product accountability records throughout the course of the study. This person will document 
the amount of investigational product received from Arrowhead Pharmaceuticals, Inc. and the 
amount administered to participants. A non-blinded Clinical Research Associate (CRA) will 
perform initial and ongoing study drug accountability. The non-blinded CRA will protect the 
integrity of the assignment blind and will not participate in data review for study participants. 
Used vials of ARO-ENaC will be retained sequestered per participant and cohort (where 
allowable by local policy) and made available to the non- blinded CRA during study drug 
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A Drug Dispensing Log must be kept current and will contain the following information: 
 
• the identification of the participant to whom the drug was dispensed 
• the date(s) and quantity of the drug dispensed to the participant. 
The date and time of dose preparation and release will be maintained to support administration of 
study drug. The pharmacy will dispense the study medication and the clinical site staff will 
administer the study medication only to participants included in this study following the procedures 
set out in the study protocol and Pharmacy Manual.  Study drug administration will be documented 
on the CRFs and/or other study drug accountability record. The inventory must be available for 
inspection by the CRA during the study. Drug supplies, excluding partially used or empty 
containers, will either be collected at the end of the study by the CRA or returned by the PI or 
designee to Arrowhead Pharmaceuticals Inc. or the designated Arrowhead approved depot. 
 
9.4. 
Retention of Investigational Product Vials 
For this study, used and partially used drug vials will be retained, if allowed by local policy, for an 
adequate period to allow accountability by the CRA. No additional study drug samples will be 
retained. 
 
9.5. 
Allocation to Treatment 
All potential participants who sign an informed consent at Screening will receive a unique 6-digit 
number (i.e. a Screening Number). The first 3 digits will represent the assigned site number and will 
be the same for each participant that screens at an individual site. The next 3 digits will be assigned 
sequentially (starting with 001). For patients who are deemed eligible, this 6-digit screening number 
will become the patient’s permanent study ID number. 
 
Eligible subjects in double-blind cohorts will be allocated a unique randomization number, in 
accordance with the randomization schedule. In each of NHV Cohorts 1-4, the first two subjects 
(sentinels) will be randomized separately to one active and one PBO. Each subject will be 
assigned to either active (ARO-ENaC) or PBO treatment. The allocation of active treatment or 
PBO will be performed using a block randomization algorithm. 
 
Participants who drop out prior to their EOS visit for reasons other than an adverse event, may be 
replaced. 
 
9.6. 
Blinding and Code-Break 
Blinding of study drug/PBO assignment is critical to the integrity of this clinical trial. It is 
expected that in most cases, AEs can be properly managed without the need for unblinding. 
However, in the event of a medical event in which knowledge of an individual participant’s 
assignment is considered relevant to the participant’s well-being, treatment options and 
management, the PI, the Sponsor Medical Monitor or a documented designated treating 
physician may request unblinding of treatment assignment. PI requests to unblind will be 
directed to the Medical Monitor. The randomization schedules will be maintained under 
controlled access. The personnel involved in the dispensing of investigational products will be 
accountable for ensuring compliance to randomization schedules. The non-blinded CRA will 
review the randomization schedule in comparison to the dispensing log to verify correct 
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If the PI considers an adverse event to be of such severity as to require immediate specific 
knowledge of the identity and dose of the relevant product, unblinding will be completed via 
IWRS system. The ‘Medical Emergency Unblinding’ form in IWRS is only accessible to the 
designated unblinded Pharmacist, PI and Sub-I. The study monitor should be informed 
promptly. 
 
If a participant requires emergent unblinding (with or without a discussion between the PI and the 
Medical Monitor preceding the unblinding), the PI may also be required to complete a ‘Drug 
Safety Unblinding Request/Notification Form’ to document the medical rationale necessitating the 
unblinding. This form is then forwarded to the local Medical Monitor. 
 
After the completion of the final study visit for each cohort, unblinding for Sponsor analysis will 
occur at Sponsor discretion. Additionally, after all subjects in CF cohort 6 have completed the Day 
43 study visit and all subjects from other cohorts have completed EOS, Sponsor will be unblinded 
for the purpose of conducting a primary analysis. After all subjects in all cohorts have completed 
their EOS visit, all cohorts may be unblinded. 
10. 
STUDY METHODS AND SCHEDULES 
10.1. Overview of Procedures 
Normal Healthy Volunteers 
While ARO-ENaC is intended for use in CF patients, these patients suffer from frequent disease 
exacerbations and are frequently on multiple concomitant medications. For this reason, this study 
initially evaluates each dose level in a healthy volunteer population to generate a baseline understanding 
of safety in a population with normal physiology and without the confounding factor of concomitant 
medication use. 
For NHVs, 4 cohorts of 6 eligible subjects (4 active: 2 PBO) will be evaluated at each dose level 
starting with Cohort 1. Cohort 5 will include 12 eligible subjects (8 active: 4 PBO) who will be 
treated with a dose equal to or less than that given to Cohort 4, with the purpose of collecting 
bronchoscopic samples to evaluate for αENaC mRNA knockdown. Participants who have signed an 
IRB/EC approved informed consent form and have met all of the protocol eligibility criteria during 
screening, will be randomized to receive ARO-ENaC or PBO. NHV cohorts will receive a single 
cycle of three doses all at a fixed dose level and administered daily on Days 1, 2, 3. 
NHV cohorts 1-4 will begin with administration of ARO-ENaC or PBO to two sentinel participants 
(one ARO-ENaC, one PBO). Following the Day 4 evaluation in these participants, if there are no 
significant safety concerns based on PI’s judgement, the remaining participants in the cohort will 
be dosed. Cohort 5 will not utilize sentinel participants as the dose evaluated in cohort 5 will be 
equal to or lower than doses used in cohorts 1-4. Dosing of participants will be staggered by at 
least 30 minutes such that no two participants will be dosed simultaneously, blood samples will be 
drawn pre-dose on Day 1 for baseline measurements. 
Based on observations for all NHV subjects in each of cohorts 1-4 through Day 21, and experience 
from any prior cohorts (i.e. all cumulative available safety data), the DSC will meet to vote on the 
following (See Fig. 1): 
1. Dose escalation to next NHV cohort 
2. Initiation of CF cohort (Cohorts 2b-4b) when applicable per Figure 1. 
Escalation to the next highest dose level in NHVs will proceed in cohorts of 6 until the highest 

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planned dose level is completed, or the trial is halted prematurely by the PI, DSC or Sponsor due to 
safety or other concerns. 
Following an affirmative vote from the DSC meeting held during NHV cohort 4 allowing the opening 
of CF Cohort 4b, NHV cohort 5 may also be subsequently opened for accrual. The primary purpose of 
cohort 5 will be to assess the effect of ARO-ENaC on αENaC mRNA expression, with samples 
obtained via bronchoscopy. The dose in cohort 5 will be equivalent to or less than the dose utilized 
in cohort 4. Based on available safety data reviewed during prior DSC meetings, the Sponsor or DSC 
may adjust the dose in cohort 5 downward. 
The DSC will consist of at least one study Investigator, Sponsor Medical Monitor, Sponsor 
pharmacovigilance lead, and an independent physician experienced in Phase 1 clinical trials. 
 
Cystic Fibrosis Patients 
Cohorts 2b, 3b, 4b will enroll eligible CF patients who have signed an IRB/EC approved informed 
consent form to receive two cycles of ARO-ENaC or PBO administered daily on Days 1, 2 and 3, 
then again on Days 22, 23 and 24. Screening for the CF cohorts can begin once Cohort 2 dosing has 
commenced but dose administration may not proceed until after the DSC has opened the designated 
CF patient cohort. CF patient cohorts 2b, 3b, and 4b will be opened for accrual once the corresponding 
NHV cohort receiving the same dose level has reached Day 21 and based on DSC vote that it is safe 
to proceed. CF patient cohorts 2b, 3b, and 4b will enroll in sequence with 2b enrolling first, followed 
by 3b, and then Cohort 4b. 
 
Once all subjects in CF cohort 4b have completed the Day 29 study visit, the DSC will meet to 
review all cumulative safety data to date and to vote on initiation of CF cohort 6. Following an 
affirmative vote from this DSC meeting, CF cohort 6 may be opened for accrual. The purpose of 
cohort 6 is to assess the safety and efficacy of an alternate dosing regimen. In CF cohort 6, the 3- day 
dosing cycle used in cohort 4b is compressed to a single dose, which is given at 2 week intervals, 
such that subjects will be dosed on Days 1, 15, and 29. The dose given on each dosing day to a 
subject in CF cohort 6 (in respirable delivered dose [RDD] terms, which represents the amount of 
drug that reaches the lung, as opposed to the amount of drug loaded into the nebulizer) will be ≤ 3x 
the dose given on each dosing day to a subject in CF cohort 4b. Thus, the dose (in RDD terms) given 
on Day 1 to a subject in cohort 6 will be ≤ the total cumulative dosage given over Days 1, 2, and 3 to 
a subject in cohort 4b. Of note, the RDD does not scale identically to the nebulizer loaded dose (i.e. 
tripling the RDD does not necessarily result in tripling the nebulizer loaded dose). 
 
Blinding (where applicable) will be preserved to the extent possible. However, treatment un- blinding 
may occur, at PI or Medical Monitor discretion, where deemed necessary for treatment of an AE or 
for a decision to be made regarding trial continuation. After all subjects in a cohort (except cohort 6) 
have completed an EOS visit, Sponsor may be unblinded to that cohort. PI and study participants will 
remain blinded.  
 
Primary analysis is planned when both all subjects in cohort 6 have completed the Day 43 study visit and 
all subjects from other cohorts have completed EOS. PIs and study participants will remain blinded through 
EOS. Sponsor will be unblinded to analyze both safety and efficacy endpoints for all NHV and CF cohorts. 
Final Analysis is planned when all subjects ended the study and the database is locked. Safety and efficacy 
results will be updated based on complete database in final analysis. 
Please refer to the dose escalation schedule outlined in Figure 1. 
 
 

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During the study (according to the SOA listed in Tables 1.1 – 1.4), participants will undergo the 
following evaluations at regular intervals: medical history review, physical examinations, vital sign 
measurements (blood pressure, temperature, heart rate, respiratory rate, pulse oximetry), weight 
measurement, AE monitoring, ECGs, Chest X-rays, Spirometry, urine pregnancy tests (females of 
childbearing potential), and concomitant medication review. Blood and urine samples will be 
collected for clinical laboratory analysis. Blood and urine samples will also be collected for 
pharmacokinetic and immunogenicity analysis, as well as for plasma metabolite identification and 
urine excretion and metabolite identification. In addition, NHV participants in Cohort 5 will undergo 
bronchoscopies. Furthermore, CF patients will be tested for Lung Clearance Index, assessment and 
reporting of CF pulmonary exacerbations, undergo CF genotyping and sweat chloride testing, and 
complete a CF questionnaire. 
 
Patient visits to the clinical facility will occur as per the SOA. Clinically significant changes 
including AEs will be followed until resolution is achieved or considered medically stable. Refer to 
the SOA for additional information. 
The PI (or medically qualified designee) will be required to remain within the clinical study 
facility for 2 hours on dosing days and will remain on call for the duration of the study. 
Participants should refrain from strenuous physical activities throughout the study. 
 
10.2. Selection and Screening
Prior to commencement of any screening procedures, the PI, or designee, will inform the 
participant about the nature and purpose of the study, including the risks and benefits involved, 
possible AEs, the fact that their participation is voluntary and provide a copy of the EC/IRB - 
approved Informed Consent Form for review. Each participant will acknowledge receipt of this 
information by giving written informed consent for their involvement in the study in the presence 
of the PI, or designee, who will also sign and date the Informed Consent Form. Time of consent 
will be recorded in the site’s source documents and reflected in the eCRFs. The original signed 
consent form will be retained by the PI and a copy of the original will be given to the participant. 
Informed consent will be performed per the Principles of the International Conference on 
Harmonisation (ICH) Good Clinical Practice (cGCP) procedures. 
 
Having given Informed Consent, potential participants will undergo procedures outlined in the 
SOA, to be performed within 28 days of the scheduled dosing date, to determine that they meet 
the inclusion/exclusion criteria specified in Sections 8.2 and 8.3. 
 
If a subject were to fail a particular Screening assessment due to a condition which may change over 
time, then the subject may be allowed to repeat the failed Screening assessment one additional 
time to establish eligibility and will be deemed not eligible if that Screening assessment is failed 
the second time. Any repeat Screening assessment must be performed within the specified 28-day 
Screening window. A subject who is deemed not eligible for the study following completion of 
Screening may subsequently re-enter Screening, with the opening of a new Screening window and 
full repeat of Screening assessments, at a future date. 
10.3. On-Study Procedures/Assessments 
 Demographics/Medical History 
Medical History will include previously diagnosed medical conditions, medication use over the 
previous 30 days, including vitamins, over-the-counter medications, prescription drugs, 

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recreational drugs or supplements and alcohol and tobacco use. 
 Physical Exam 
A complete physical exam will be performed at Screening and Day 1 (pre-dose) with a symptom 
directed physical exam performed after Day 1. Areas examined include: 
x Constitutional 
x Skin 
x HEENT 
x Heart 
x Lungs 
x Back 
x Abdomen 
x Extremities 
x Mental Status 
x Neuro (gait/reflexes) 
x Additional examination may be performed at PI discretion 
 Electrocardiogram 
A single 12-lead ECG measurement will be obtained at time points outlined in the SOA after the 
participant is semi-supine for at least 3 minutes. On dosing days ECGs will be performed pre- dose 
and 2 hours post-dose and may be performed more frequently if indicated. ECGs should be 
performed prior to other invasive procedures such as blood draws. Any abnormal ECGs will be 
repeated in triplicate, with each measurement approximately 1 minute apart. 
 Chest X-ray 
Chest radiographs will be performed as per SOA and in the event that a healthy volunteer or CF 
patient experiences AEs involving lower lung infection, dyspnea, bronchospasm or CF 
exacerbation. 
 Vital Sign Assessments 
Systolic/diastolic blood pressure, temperature, heart rate, respiratory rate (breaths/min) and pulse 
oximetry will be obtained at time points outlined in the SOA after the participant is semi-supine 
for at least 3 minutes. Vitals signs will be obtained prior to venipuncture and other invasive 
procedures. 
 Clinical Laboratory Tests 
Blood and urine samples will be collected to perform clinical laboratory tests. Participants will be 
required to fast at least 8 hours for the screening and at least 4 hours for other sample collections. 
Within the screen period, up to 28 days prior to the first dose of study medication, a blood and 
urine sample will be collected for the laboratory tests detailed below to establish baseline data and 
eligibility for enrolment. The results will be assessed by the PI, or medically qualified designee, 
before study enrollment. Any abnormality in laboratory values i.e., those that would jeopardize the 
safety of the participant or impact on the validity of the study results (that are confirmed on repeat) 
deemed clinically significant by the PI, or medically qualified designee will result in exclusion of 
that participant. Clinical laboratory tests will be performed on participants’ blood and urine at 
specified time-points listed in the SOA. 
x Biochemistry: Sodium, potassium, chloride, bicarbonate, glucose, urea, creatinine (including 

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eGFR), creatine kinase, troponin-I, phosphate, total calcium, albumin, total protein, total 
bilirubin, lipase and amylase, conjugated bilirubin, gamma glutamyltransferase (GGT), 
alkaline phosphatase (ALP), alanine aminotransferase (ALT), aspartate transaminase (AST), 
and hemoglobin A1C 
• Hematology: Hemoglobin, red blood cell count (RBC), hematocrit, mean cell volume 
(MCV), mean cell hemoglobin (MCH), mean cell hemoglobin concentration (MCHC), 
platelets, white cell count, neutrophils, lymphocytes, monocytes, eosinophils and 
basophils 
• Coagulation: Partial thromboplastin time (PTT), Prothrombin time (PT) with INR 
• Urinalysis: Leucocytes, nitrites, urobilinogen, protein, pH, blood, specific gravity, 
ketone, bilirubin and glucose. Urine electrolytes will also be collected, stored and 
analyzed as needed. 
• Microscopic urinalysis will be performed if indicated: white blood cells, red blood cells, 
epithelial cells, bacteria 
• 24 hour urine: Aldosterone, sodium, potassium 
• Serology: Hepatitis B surface antigen, Hepatitis C antibody and HIV antibody screen. If 
necessary, participants will be counseled by the PI, or medically trained designee, 
concerning the blood tests for Hepatitis B surface antigen, Hepatitis C and HIV antibodies, 
and their subsequent results. 
• FSH: Post-menopausal status will be confirmed by follicle-stimulating hormone (FSH) 
level consistent with post-menopausal state. 
• Pregnancy: Females of childbearing potential will have a urine pregnancy test at 
Screening and pre-dose on the first dosing day of each cycle. If urine pregnancy test is 
positive, dosing should not occur, and the patient will be referred to their primary care 
provider for follow up. 
• Drug and Alcohol Use Screen: Urine drug screen for Benzodiazepines, Amphetamines, 
Barbiturates, Methamphetamines, Methadone, Opiates, Phencyclidine, Cannabinoids, 
MDMA and Cocaine. Alcohol Breath Test will be done to test for alcohol consumption. A 
positive alcohol breath test should prompt further discussion about quantity and frequency 
of alcohol consumption to assess whether the subject meets the alcohol- related exclusion 
criteria. 
• Immunogenicity: Specified subjects will be assessed for anti-drug antibodies as per 
SOA. 
• Genotype: All CF patient cohorts will be assessed for mutations causative or otherwise 
known to influence Cystic Fibrosis, specifically CFTR and ENaC variants with the 
subject’s written consent. If not completed at Screening, blood draws for genotype 
evaluation may be completed anytime during the study. 
• Sweat chloride: All CF patients will undergo a sweat chloride assessment, if the test is 
available at the patient’s study site. If not able to be completed at Day 1, sweat chloride 
evaluation may be completed anytime during the study as there is no expectation that 
study drug treatment should alter sweat chloride levels. 
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purposes or as otherwise specified. If Day 1 or as otherwise specified values are erroneous or 
not available and repeat blood draw is not possible, the pre-dose value closest to Day 1 (e.g., 
Screening) may be used as baseline. 
 Spirometry, CFQ-R and Lung Clearance Index 
x Spirometry: Spirometry will be evaluated per SOA in healthy volunteers and in CF 
patients. Spirometry will be conducted in accordance with ATS-ERS guidelines 
(Graham 2019). Sites are required to perform spirometry measurements to achieve three 
acceptable FEV1 and FVC measurements at each timepoint noted in the protocol 
Schedule of Assessments (SOA). The largest FVC and the largest FEV1 observed from 
all of the acceptable values are to be reported in the clinical database, even if they do not 
come from the same maneuver. Their ratio is used for the FEV1/FVC ratio calculation. 
All measurements must be documented in the source/progress notes. The required 
spirometer range to use is NHANES III. In NHVs, spirometry will be performed at a 
single site. While multiple sites will be utilized to enroll CF patient cohorts, spirometry 
will be measured in an individual patient at the same facility and with the same 
spirometry equipment throughout the study. 
Bronchodilator will not be given to either NHVs or CF patients as part of the spirometry 
assessment. However, there may be NHVs and CF patients who use bronchodilators as 
concomitant medications during the study. With that in mind, pre-bronchodilator 
spirometry is defined as a spirometry measurement which is performed after subjects have 
both: 
o Withheld short-acting bronchodilator(s) (either short-acting beta-agonist or short-
acting muscarinic antagonist) for at least 4 hours prior to spirometry 
o Withheld long-acting bronchodilator(s) (either long-acting beta-agonist or long- acting 
muscarinic antagonist) for at least 12 hours prior to spirometry 
Post-bronchodilator spirometry is defined as a spirometry measurement that is 
performed which does not meet these criteria (i.e. a subject has used a short-acting 
bronchodilator within the prior 4 hours and/or a long-acting bronchodilator within the 
prior 12 hours). 
For the Screening assessment, either pre-bronchodilator or post-bronchodilator 
spirometry is acceptable. 
 
For all other (i.e. non-Screening) assessments, the initial spirometry assessment of the 
visit should be a pre-bronchodilator spirometry measurement. If a subject fails to 
withhold bronchodilator(s) appropriately in order to accomplish a pre-bronchodilator 
measurement on a given assessment day, then the following considerations apply: 
o If a subject’s Day 1 (pre-dose) baseline spirometry measurement is pre- bronchodilator 
but the subject fails to withhold bronchodilator on a subsequent visit day, then post-
bronchodilator spirometry should be performed on that visit day only 
o If a subject fails to withhold bronchodilator on the Day 1 (pre-dose) baseline 
spirometry measurement, then the Day 1 spirometry measurement should proceed as a 
post-bronchodilator measurement. Importantly, all subsequent spirometry 
measurements for that subject should also be performed post-bronchodilator 
o Each spirometry assessment will be recorded in the source documents as pre- or post-

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bronchodilator 
Finally, the above considerations only apply to the initial spirometry assessment of a 
visit. On dosing days, subjects will also undergo repeat (post-dose) spirometry 
assessments. Those post-dose spirometry assessments may be either pre-bronchodilator 
or post-bronchodilator, which should be recorded in the source documents. In CF 
patients, the initial spirometry assessment of a visit will be used for efficacy assessments, 
while the post-dose spirometry measures will be used as safety assessments. 
• Cystic Fibrosis Questionnaire-Revised (CFQ-R): The questionnaire provides 
information about demographics, quality of life and daily activities. Subjects will be 
asked to complete the CFQ-R in their native language if valid translations are available. If 
there is no validated translation then the subject will not complete the questionnaire. 
Copies of the CFQ-R will be provided in the study Procedural Manual. 
• Lung Clearance Index (LCI): LCI is a measure derived from multiple breath washout 
(MBW) test which provides an assessment of ventilation heterogeneity, and is defined as 
the cumulative expired volume at the point where end-tidal inert gas concentration falls 
below 1/40th of the original concentration, divided by the functional residual capacity 
(FRC). LCI with be evaluated per SOA in CF patients only and LCI will be measured in 
any individual patient at the same site. For CF cohorts 2b, 3b, and 4b, at every study visit 
where LCI is measured per SOA, the site is asked to provide three acceptable tests. For 
CF cohort 6, at every study visit where LCI is measured per SOA, the site is asked to 
provide two acceptable tests (fewer tests in this cohort due to the increased length of the 
assessment in those with more severe lung disease). For data analysis, the results of all 
acceptable tests will be averaged. Thus, if a site provides either more or less than the 
requested number of acceptable tests, all acceptable data will be used for analysis. Test 
should be performed in accordance with the ERS/ATS consensus statement for inert gas 
washout measurement. This test will be performed at all sites when available. 
 
Bronchodilator will not be given to CF patients as part of the LCI assessment. However, 
there may be CF patients who use bronchodilators as concomitant medications during the 
study. With that in mind, pre-bronchodilator LCI is defined as a LCI measurement which 
is performed after subjects have both: 
o Withheld short-acting bronchodilator(s) (either short-acting beta-agonist or short- 
acting muscarinic antagonist) for at least 4 hours prior to LCI 
o Withheld long-acting bronchodilator(s) (either long-acting beta-agonist or long- acting 
muscarinic antagonist) for at least 12 hours prior to LCI 
Post-bronchodilator LCI is defined as a LCI measurement that is performed 
which does not meet these criteria (i.e. a subject has used a short-acting bronchodilator 
within the prior 4 hours and/or a long-acting bronchodilator within the prior 12 hours). 
 
All LCI assessments should be pre-bronchodilator. If a subject fails to withhold 
bronchodilator(s) appropriately in order to accomplish a pre-bronchodilator 
measurement on a given assessment day, then the following considerations apply: 
o If a subject’s Day 1 (pre-dose) baseline LCI measurement is pre-bronchodilator but the 
subject fails to withhold bronchodilator on a subsequent visit day, then post-
bronchodilator LCI should be performed on that visit day only 

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o If a subject fails to withhold bronchodilator on the Day 1 (pre-dose) baseline LCI 
measurement, then the Day 1 LCI measurement should proceed as a post- 
bronchodilator measurement. Importantly, all subsequent LCI measurements for that 
subject should also be performed post-bronchodilator 
o Each LCI assessment will be recorded in the source documents as pre- or post- 
bronchodilator 
 Bronchoscopies
Subjects will be required to fast beginning at midnight the night before the procedure. Following 
sedation with fentanyl and midazolam (or as per local sedation standards), the bronchoscope will be 
introduced into the airway and topical anesthesia with xylocaine or lidocaine will be applied to the 
airway. Subsequently, bronchoalveolar lavage (BAL) and bronchial brushing samples will be 
obtained. Bronchial brushings will be obtained first. 
Bronchial brushings: Small airway brushings will be obtained. The bronchoscope will be wedged 
into a subsegment of the right lower lobe (see Banerjee 2009 for reference). A sheathed cytology 
brush will be passed down the working channel of the bronchoscope and then unsheathed under 
fluoroscopic guidance with the brush tip lying 2-3 cm from the pleural surface. Small airway 
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saline. The liquid will be centrifuged and the cell pellet will be frozen and stored. The cell pellet 
will be utilized for measurement of DENaC expression. 
BAL: The bronchoscope will be wedged into a subsegment of the right middle lobe and also into a 
subsegment of the lingula. In each subsegment, 2 x 50 mL aliquots of normal saline will be instilled 
and then withdrawn via suction (2 aliquots from right middle lobe and 2 aliquots from lingula). 
Thus, a total of 200 mL of saline will be instilled into the lungs. BAL fluid will be centrifuged and 
the resultant supernatant will be collected, frozen and stored. BAL cells will be utilized for cell 
count and differential. BAL supernatant will be used for measurement of cytokine concentrations 
(including IL-1E, IL-6, IL-8, and TNFD), as well as for measurement of DENaC expression in BAL 
exosomes. An aliquot of BAL fluid will be saved for future research purposes upon the decision of 
the Sponsor. 
Data from the Day 0 bronchoscopy assessment will be used as the baseline value. 
Further details on handling of bronchoscopy specimens will be available in the Central Laboratory 
Manual. 
 Pharmacokinetics
Samples (blood and urine) for analysis of circulating ARO-ENaC will be obtained at time points 
following study drug administration as outlined in the SOA. ARO-ENaC metabolites will be 
identified in pooled samples taken at timepoints per the SOA. 
10.3.9.1 Blood Sample Collection, Processing, and Analysis 
Blood samples from participants will be collected at time points outlined in the SOA through an 
indwelling cannula or through a fresh vein puncture. The actual blood collection time will be 
recorded in the source documents. In all such cases, appropriate time corrections, for the actual 
time of sample collection will be incorporated at the time of data analysis. 
The actual sample times will be recorded in the eCRF and will be entered at the time of or as 
soon as possible after sampling. All times must be recorded in the 24-hour format. An 
explanation must be given for any blood sample taken outside of the set sampling times. 

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Whole blood will be collected and processed per the Laboratory Manual.  
To avoid hemolysis which can yield a falsely elevated potassium level: 
x 
Mix tubes with anticoagulant additives gently 5-10 times 
x 
Avoid drawing blood from a hematoma 
x 
Avoid drawing the plunger back too forcefully, if using a needle and syringe, or too small a 
needle, and avoid frothing of the sample
x 
Make sure the venipuncture site is dry 
x 
Avoid a probing, traumatic venipuncture 
x 
Avoid prolonged tourniquet application or fist clenching 
*Any sample with suspected hemolysis should be redrawn and not processed. 
 
*Any patient with hyperkalemia reported should be called back for repeat blood draw 
immediately upon receipt of result. 
10.3.9.2 Urine Sample Collection, Processing and Analysis 
Urine samples from participants will be collected at time points outlined in the SOA. For spot 
urine collection, the actual urine collection time and volume will be recorded. For interval sample 
collections, the start and stop time of urine sample collection (along with volume) will be recorded 
with an attempt to void at the end of the collection interval. All times must be recorded in the 24-
hour format. An explanation must be given for any sample taken outside of the set sampling times. 
Urine will be collected and processed per the Laboratory Manual. 
 Concomitant Medications/Therapies 
Participants will be instructed to inform the PI of the details (indication, dose and dates of 
administration) if they do take any medication, and these details will be recorded in the CRF. 
Paracetamol may be used during the study only as necessary. CFTR modulators/correctors and 
other CF standard of care medications are allowed but patients should stay on the same regimen 
for the duration of the study. 
 Early Termination Procedures 
The reason for Early Termination will be documented in source documents and eCRF. Procedures 
as outlined in the SOA will be completed. 
10.4.
Allocation of Treatment 
Participants will receive study drug by assigned cohort. Treatments will be administered per the 
randomized sequence (where applicable) kept by the pharmacy or in a secure place at the clinical 
site, under control of the un-blinded staff member. 
 
Details of dose volume to be administered to achieve the specified pulmonary delivered dose are 
presented in the Pharmacy and Study Procedure Manuals. 
10.5. Study Treatment Administration & Timing of Procedures 
Appropriately trained employees of the clinical site will administer the study treatment. Each 
dose will be administered as inhaled nebulized solution. The date, time and location of 
administration will be recorded in the source notes. 

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Actual times of procedures for each participant will vary depending on scheduling and will be 
recorded in the CRF. 
In the event of multiple procedures scheduled at the same time, non-invasive procedures (i.e., 
ECGs, AE assessment) will be conducted prior to invasive procedures (i.e., blood sample 
collection). Timing of activities may be adjusted slightly to accommodate all procedures. 
10.6. Pregnancy Testing and Contraception Requirements 
Female participants of childbearing potential will have urine pregnancy tests at the Screening 
and Day 1 (baseline) visits, prior to dosing throughout the study, and at completion of the study 
as indicated in Tables 1.1-1.4. Females not of childbearing potential must be either surgically 
sterile or postmenopausal (defined as cessation of regular menstrual periods for at least 12 
months without an alternative medical cause) with supportive FSH consistent with 
postmenopausal state based on laboratory reference ranges. If a subject’s urine pregnancy test is 
positive, the participant will be referred to their primary care provider for follow-up. Female 
participants with a positive pregnancy test at Screening or on Day 1 predose will not be enrolled 
in the study. Female participants who become pregnant after Day 1 will not receive any 
subsequent administration of IP but may otherwise continue in the study. 
All participants (female participants of childbearing potential with male partners and male 
participants with female partners of childbearing potential) must consent to use highly effective 
contraception during the study and for at least 12 weeks following the end of study or last dose 
of IP, whichever is later. Males must not donate sperm during the study and for at least 12 
weeks following the end of the study or last dose of IP, whichever is later. Highly effective 
contraception is: 
• Using twice the normal protection of birth control by using a condom AND one other form 
of contraception; either birth control pills (The Pill), or injectable birth control, birth control 
patch or contraceptive implant associated with inhibition of ovulation, or intrauterine device; 
• Surgical sterilization as a single form of birth control: ie, tubal ligation, hysterectomy, 
bilateral oophorectomy, vasectomy or equivalently effective surgical form of birth control; 
• True sexual abstinence for the duration of the study and for at least 12 weeks following the 
end of study or after the last dose of IP, whichever is later, is acceptable only when in line 
with the preferred and usual lifestyle of the participant. Periodic abstinence (calendar, 
symptothermal, postovulation methods), withdrawal (coitus interruptus), spermicides only, 
and lactational amenorrhea methods are not considered “true” abstinence and are not 
acceptable methods of contraception. 
Highly effective contraception is to begin at least 7 days prior to initial dosing of IP. 
10.7. Safety Assessments 
The safety of ARO-ENaC will be evaluated by collection of the following measurements 
performed at time points as specified in the SOA as well as CS changes from baseline to 
scheduled time points: 
• Monitoring of AEs/SAEs 
• Physical examinations 
• Vital signs 
• ECG measurements 
• Chest X-rays 
• Measurement of serum and urine electrolytes 

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• Spirometry 
• Clinical laboratory tests (hematology, chemistry, coagulation, urinalysis) 
• Concomitant medications/therapy 
• Reasons for treatment discontinuation due to toxicity 
The AE/SAE reporting period for an enrolled participant will begin when the participant 
provides informed consent. Treatment-Emergent AEs/SAEs will be those defined as following 
dose administration. All AEs/SAEs that occur during the AE reporting period specified in the 
protocol must be reported to Arrowhead Pharmaceuticals, Inc. regardless of the relationship of 
the AE to study treatment. Any known untoward event that occurs beyond the AE reporting 
period that the PI considers an SAE and possibly related to study treatment will be reported to 
Arrowhead. 
11. 
ADVERSE EVENTS 
The PI and clinical facility staff are responsible for detection, recording and reporting of events 
that meet the criteria and definition of various AEs as listed below. Adverse events will be 
recorded from time of signed consent through to EOS; only AEs that occur post-dose will be 
considered treatment-emergent. The PI and clinical facility staff are responsible for detection, 
recording and reporting of pregnancy and appropriate follow up. Any known pregnancy that occurs 
within 90 days following the end of study visit should be reported by the subject to the PI. 
Information regarding any reported pregnancy should be collected for at least 1 year after birth or 
longer if it is decided that additional follow-up is required or until the end of the pregnancy. 
11.1. Definitions 
An Adverse Event (AE) is any untoward medical occurrence in a patient or clinical investigation 
patient administered a pharmaceutical product and which does not necessarily have to have a 
causal relationship with this treatment. An AE can therefore be any unfavorable and unintended 
sign (including an abnormal laboratory finding or diagnostic test), symptom, or disease temporally 
associated with the use of a medicinal (investigational/experimental) product, whether related to 
this product or not. (Refer to ICH E2a: Clinical Safety Data Management: Definitions and 
Standards for Expedited Reporting, 27 October 1994). 
 
Treatment-emergent AEs will be defined as AEs with onset after administration of the study 
drug, or when a pre-existing medical condition increases in severity or frequency after study 
drug administration. 
AEs will not include: 
• A medical procedure such as surgery, endoscopy, tooth extraction, or transfusion 
(although the condition that leads to the procedure may be an AE) 
• A pre-existing disease or condition present at the start of the study that does not worsen 
during the study 
• Any situation where an untoward medical occurrence has not occurred (for example, 
hospitalizations for cosmetic elective surgery or “social” admissions) 
• An overdose of either the investigational product or a concurrent medication without any 
resulting signs or symptoms 
A Serious Adverse Event (SAE) is an AE that: 
• Results in death 

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• Is life-threatening (NOTE: The term ‘life-threatening’ in the definition of ‘serious’ refers 
to an event/reaction in which the participant was at immediate risk of death at the time of 
the event/reaction; it does not refer to an event/reaction which hypothetically might have 
caused death, if it were more severe) 
• Requires inpatient hospitalization or prolongation of an existing hospitalization 
• Results in persistent or significant disability/incapacity 
• Is a congenital anomaly/birth defect 
• Is a medically important event or reaction 
Medical and scientific judgment should be exercised in deciding whether other situations should 
be considered serious such as important medical events that may not be immediately life- 
threatening or result in death or hospitalization but might jeopardize the participant or might 
require medical or surgical intervention to prevent one of the other serious outcomes listed in the 
above definition. These should also be considered serious. Examples of such events are intensive 
treatment in an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency or drug 
abuse. 
 
11.2. Clinical Laboratory Abnormalities and Other Abnormal Assessments as AEs 
Abnormal assessments (e.g., ECGs and vital signs) that are judged by the PI as clinically 
significant (CS) or result in clinical sequelae will be recorded as AEs. Laboratory abnormalities 
will be reported by the PI as AEs if the abnormality is considered CS or results in clinical 
sequelae. All laboratory abnormalities reported as AEs should by recorded as CS in the laboratory 
database. 
 
Clinically significant abnormal laboratory findings or other CS abnormal assessments that are 
detected during the study or are present at baseline and significantly worsen following the start 
of the study will be reported as AEs. 
 
The PI (or medically qualified designee) will exercise his or her medical and scientific judgment 
in deciding whether an abnormal laboratory finding or other abnormal assessment is CS. 
 
11.3. Timing, Frequency, and Method of Detecting AEs 
Any pre-existing conditions or signs and/or symptoms present in a participant prior to the start of 
the study (i.e., before informed consent) should be recorded as Medical/Surgical History. 
 
All AEs occurring after informed consent and on or before the final visit must be reported as AEs; 
only AEs that occur post-dose will be considered treatment-emergent. All AEs must be recorded 
irrespective of whether they are considered drug-related. AEs will be collected through the EOS.  
At each visit/assessment in the period defined above, AEs will be evaluated by the PI (or 
medically qualified designee) and recorded. 
11.4. Recording of AEs 
When an AE occurs, it is the responsibility of the PI or medically qualified designee to 
review all documentation (e.g., hospital progress notes, laboratory, and diagnostics reports) 
relative to the event. The PI or medically qualified designee will then record the AE on the 
AE CRF. Additional reporting requirements for an AE that meets serious criteria are 

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discussed in Section 11.7 below. 
The PI or medically qualified designee will attempt to establish a diagnosis of the event based on 
signs, symptoms, and/or other clinical information. In all cases, when available, the diagnosis 
should be reported as the event and not the individual signs/symptoms. It is not acceptable for the 
PI to send photocopies of the patient’s medical records to the Sponsor in lieu of completion of the 
appropriate AE eCRF pages. 
11.5. Evaluating AEs 
 Assessment of Severity 
The PI or medically qualified designee will assess severity for each AE reported during the 
study. The assessment will be based on the PI’s (or medically qualified designee’s) clinical 
judgment. The severity of all AEs should be assigned to one of the following categories: 
x Mild: An event that is easily tolerated by the participant, causing minimal discomfort and 
not interfering with everyday activities. 
x Moderate: An event that is sufficiently discomforting to interfere with normal everyday 
activities. 
x Severe: An event that prevents normal everyday activities. 
An AE that is assessed as severe should not be confused with an SAE. Severity is a category 
utilized for rating the severity of an event; and both AEs and SAEs can be assessed as severe. 
An event is defined as ‘serious’ when it meets one of the predefined outcomes as described in 
Section 11.1. 
 Assessment of Causality 
The PI (or medically qualified designee) is obligated to assess the relationship between 
investigational product and the occurrence of each AE. The PI (or medically qualified designee) 
will use clinical judgment to determine the relationship. Alternative causes, such as natural history 
of the underlying diseases, concomitant therapy, other risk factors, and the temporal relationship 
of the event to the investigational product will be considered and investigated. The PI (or 
medically qualified designee) will also consult the Investigator’s Brochure in the determination of 
his/her assessment.
There may be situations when an SAE has occurred and the PI has minimal information to 
include in the initial SAE report. However, it is very important that the PI (or medically 
qualified designee) always assess causality for every event prior to transmission of the SAE 
report form. The PI (or medically qualified designee) may change his/her opinion of causality 
considering follow-up information, amending the SAE report form accordingly. The causality 
assessment is one of the criteria used when determining global regulatory reporting 
requirements. 
The PI (or medically qualified designee) will provide the assessment of causality utilizing three 
possible categories: Not Related, Possibly Related and Probably Related. 
An AE will be considered “not related” to the use of the product if any of the following tests are 
met: 
x An unreasonable temporal relationship between administration of the product and the 
onset of the AE (e.g., the event occurred either before, or too long after administration of 
the product for it to be considered product-related) 
x A causal relationship between the product and the AE is biologically implausible (e.g., 

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death as a passenger in an automobile accident) 
 
x A clearly more likely alternative explanation for the AE is present (e.g., typical adverse 
reaction to a concomitant drug and/or typical disease-related event) 
 
An AE will be considered “Possibly related” when an event follows a reasonable temporal 
sequence from administration of the study drug, but which could also be explained by 
concurrent disease or other drugs or chemicals. Or an event that follows a known or 
expected response pattern to the drug but that could have been produced by a number of 
other factors. 
 
An AE will be considered “Probably related” when an event follows a reasonable temporal 
sequence from administration of the IP, unlikely to be attributed to concurrent disease or other 
drugs or chemicals. Also, an event that follows a known or expected response pattern to the IP, or 
that is confirmed by stopping or reducing the dosage of the IP and that could not reasonably be 
explained by known characteristics of the participant’s clinical state. 
 
11.6. Follow-up of AEs 
After the initial AE, the PI is required to proactively follow each participant and provide further 
information on the participant’s condition as deemed appropriate. 
 
All AEs will be followed until resolution, until the condition stabilizes, until the event is otherwise 
explained, or until the participant is lost to follow-up. Once resolved, the appropriate AE eCRF 
page and SAE report form (if event is serious) will be updated. The PI, or medically qualified 
designee, will ensure that follow-up includes any supplemental investigations as may be indicated 
to elucidate the nature and/or causality of the AE or SAE. This may include additional laboratory 
tests or investigations, histopathological examinations, or consultation with other health care 
professionals. In the event of a fatal outcome in an SAE, the PI, or medically qualified designee, 
will attempt to obtain postmortem findings, including histopathology, and provide all additional 
information in a follow up SAE report. 
New or updated information regarding an SAE will be recorded on a new SAE report form 
marked as follow-up with the appropriate follow-up number added to the report. The follow-up 
report will be signed and dated by the PI. 
11.7. Prompt Reporting of SAEs 
Any AE meeting serious criteria MUST be reported promptly to the Sponsor’s designated 
Pharmacovigilance Contract Research Organization (CRO), and the IRB/EC in accordance with 
applicable local/ institutional requirements. 
 Completion and Transmission of the SAE reports 
Once an Investigator becomes aware that an SAE has occurred in a study participant, she/he will 
report the information on an SAE report form to the designated Pharmacovigilance CRO within 24 
hours. The SAE report form will always be completed as thoroughly as possible with all available 
details of the event and signed by the PI (or medically qualified designee). If the PI does not have 
all information regarding an SAE, he/she will not wait to receive additional information before 
reporting the event. The SAE report form will be updated when additional information is received. 
The PI (or medically qualified designee) will always provide an assessment of causality at the 
time of the initial report as described in Section 11.5.2. However, as new information becomes 

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11.9. Post-study AEs 
A post-study AE is defined as any event that occurs outside of the AE detection period defined in 
Section 11.3. 
Investigators are not obligated to actively seek AEs in former study participants. However, if the 
Investigator learns of any SAE at any time after a participant has been discharged from the study, 
and he/she considers the event reasonably related to the investigational product, the PI will 
promptly notify the Sponsor. 
11.10. SAEs Related to Study Participation 
An SAE considered related to study participation (e.g., procedures, invasive tests, a change in 
existing therapy), even if it occurs during the pre- or post-treatment period, will be reported 
promptly (refer Section 11.7). 
12. 
DATA ANALYSIS AND STATISTICAL CONSIDERATIONS 
In general, continuous data will be summarized by descriptive statistics, including number of 
subjects, mean, standard deviation, median, minimum, and maximum. Categorical data will be 
summarized by the number and percentage of subjects. Specifics of data analysis are provided in 
the Statistical Analysis Plan. 
 
12.1. Sample Size Considerations & Stratification 
Sample sizes for NHV cohorts 1-5 and CF cohorts 2b, 3b, and 4b are decided based on the 
probability of observing at least one TEAE from each cohort. When probability of observing 
TEAE from a single subject who received active drug is 30%, chance of observing at least one 
TEAE will be higher than 75%, among 4 dosed subjects.  With cohort size 8 or 9 (cohorts 4b and 
5), probability of seeing at least one TEAE would be approximately 85% and 95% if assumed 
probabilities of observing AE from a single dosed subject are 20% and 30%, respectively. Table 5 
below lists probabilities of observing at least one TEAE under various scenarios. 
Table 5: Sample Size Calculation for Cohorts 1-5 and 2b, 3b and 4b 
Probability of observing at least 
one TEAE from each dosed 
subject 
Number of 
subjects treated 
per Cohort 
Probability of observing at 
least one TEAE from Cohort 
0.2 
4 
0.59 
0.3 
4 
0.76 
0.2 
5 
0.67 
0.3 
5 
0.83 
0.2 
6 
0.74 
0.3 
6 
0.88 
0.2 
7 
0.79 
0.3 
7 
0.92 
0.2 
8 
0.83 
0.3 
8 
0.94 

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Probability of observing at least 
one TEAE from each dosed 
subject 
Number of 
subjects treated 
per Cohort 
Probability of observing at 
least one TEAE from Cohort 
0.2 
9 
0.87 
0.3 
9 
0.96 
0.2 
10 
0.89 
0.3 
10 
0.97 
 
Figure 2: Relationship between Sample Size and Probability of Observing at Least One TEAE 
 
Sample size for cohort 6 is calculated to have more than 80% power to observe 5% absolute 
change from baseline in ppFEV1 at Day 43 at significance level 0.05, with standard deviation 7%.  
Sub-group analysis of CF patients will be conducted according to the presence of CFTR 
modulator/corrector use at baseline as well as inhaled hypertonic saline use at baseline. 
No stratification is planned in this study. 
12.2. Screening Data 
Demographics will be tabulated by participant and summarized by cohort and treatment group. 
Eligibility assessments at baseline, including medical/surgical history data and physical examination 
data (including height and weight), will be listed for each participant. 
12.3. Safety/Tolerability Data 
In general, safety analyses will be performed based on Safety Analysis Set, which include all 
enrolled subjects who receive at least one dose of study drug (placebo or active). Results will be 
summarized by population (NHV and CF) and cohort. Placebo subjects from each cohort will be 
pooled by population.  
 

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Treatment-emergent AEs will be summarized by System Organ Class (SOC) and Preferred Term 
(PT), classified from verbatim terms, with MedDRA version 23.0 or later. The incidence and 
percentage of participants with at least 1 occurrence of a PT will be included, per the most severe 
grade using a 3-point scale (mild, moderate, severe). The number of events per Preferred Term will 
also be summarized. Causality (relationship to study treatment) will be summarized separately. 
The incidence and frequency of treatment-emergent AEs, SAEs, related AEs, related SAEs and 
AEs leading to withdrawal, dose modification, or treatment discontinuation will be 
summarized by population and cohort by SOC and Preferred Terms. All AEs, SAEs will also 
be summarized in listings. The duration of AEs will be determined and included in listings, 
along with the action taken and outcome. 
Laboratory parameters will be summarized at each scheduled time point using descriptive 
statistics. The incidence of laboratory abnormalities will be summarized. Results for variables that 
are not coded will be presented in the listings as “below, within, and above” the normal limits of 
the laboratory. Pregnancy test results will be listed.  
Vital sign measurements will be summarized at each scheduled time point using descriptive 
statistics. Physical examination findings will be summarized by time point and presented in 
patient listings. 
ECG parameters at each scheduled study visit, changes from baseline and qualitative 
assessments will be summarized. 
12.4. Immunogenicity (Anti-drug Antibodies) Data 
Changes from assay negative to positive will be summarized by dose and time to positive. 
Descriptive statistics of immunogenicity parameters will include mean, SD, minimum, and 
maximum. 
12.5. Pharmacokinetic Data 
Plasma concentrations of ARO-ENaC collected at specified time points post-dose from all 
participants at different dose levels will be used to calculate the following single dose 
pharmacokinetic parameters (Table 6): 
Table 6: Definitions of Pharmacokinetic Parameters to be Assessed 
 
AUC 0-24 
The area under the plasma concentration versus time curve from 0 to 24 hours 
AUC inf 
The area under the plasma concentration versus time curve from zero to infinity 
C max 
The maximum plasma concentration will be obtained directly from the plasma 
concentration time profile 
t max 
The time to maximum plasma concentration will be obtained by inspection 
t 1/2 
The half-life will be calculated by the equation t 1/2  = ln(2)/k el 
Additional PK parameters may be calculated as needed. The pharmacokinetic parameters will be 
determined using non-compartmental method(s). Descriptive statistics of pharmacokinetic 
parameters will include mean, standard deviation (SD), and coefficient of variation (CV), 
minimum and maximum. Dose-related trends in pharmacokinetic parameters will be assessed. 
 
Pharmacokinetic parameters will be tabulated and summarized by dose level. The concentration- 
time profiles for each participant and the mean concentration-time profiles by dose level will be 
plotted with concentration presented on both linear and logarithmic scales. 
 

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Statistical analysis will be performed on the pharmacokinetic parameters using validated 
statistical software. 
12.6. Pharmacodynamic/Efficacy Data 
Descriptive statistics will be performed by scheduled study visit on the following 
measures of efficacy and pharmacodynamic activity: 
• Spirometry (ppFEV1) 
• Revised Cystic Fibrosis Questionnaire (respiratory domain) 
• Lung Clearance Index 
• Rate of CF Exacerbations 
• BMI 
• ENaC mRNA expression from bronchoscopic samples 
Efficacy data for CF patients will be analyzed by cohort. Placebo subjects from each cohort will be 
pooled. Efficacy analyses will be completed based on Safety Analysis Set, which include all 
enrolled subjects who receive at least one dose of study drug (placebo or active). CF patients will 
be analyzed in aggregate and also separately based on CFTR mutation status and based on use or 
no use of a stable regimen (last 2 months) of CFTR modulators/correctors as well as use or no use 
of inhaled hypertonic saline.  
12.7. Data Recording and Quality Control 
Source documents must be maintained for each participant in the study, consisting of all 
demographic and medical information, including clinical laboratory data, and entered into the 
EDC system within five days of the subject visit. A copy of the signed informed consent form 
must be retained. All information on the eCRFs must be traceable to these source documents in 
the participant's file. 
 
Data recorded in all participants’ eCRFs will be subjected to a quality control review. 
12.8. Handling Missing and Incomplete Data 
Partial or missing dates of adverse events and concomitant medications will be imputed. Adverse 
events with missing severity and/or possible relationship to treatment will be included in the all 
adverse events analyses, except by severity grade and treatment-related. Every effort will be made 
to obtain complete dates for deaths. Details of the imputation algorithms will be specified in the 
statistical analysis plan. 
13. 
STUDY APPROVAL AND CONDUCT 
The following conditions will be met. 
13.1. Regulatory Approval 
The requirements for the conduct of clinical trials in accordance with local applicable regulations 
will be met before commencement of this study. 
13.2. Ethics Committee (EC)/ Institutional Review Board (IRB) Approval 
Prior to initiation of the study, written EC/IRB approval of the Protocol and Informed Consent 
Forms, based on the principles of ICH cGCP procedures, will be received. A copy of the signed 
and dated letter of approval will be provided to the clinical site and Arrowhead Pharmaceuticals, 

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Inc. prior to study commencement. Any written information and/or advertisements to be used for 
volunteer recruitment will be approved by the EC/IRB prior to use. A list of the EC/IRB voting 
members, their titles or occupations, FWA number (where applicable) and their institutional 
affiliations will be requested before study initiation. 
Protocol modifications that may impact patient safety or the validity of the study will be 
approved by the IRB, following written agreement from the Sponsor. 
13.3. Ethical Considerations 
This study will be carried out per the Declaration of Helsinki 1964, as modified by the 64th World 
Medical Assembly, Fortaleza, Brazil, October 2013, the Notes for Guidance on Good Clinical 
Practice (cGCP) (2000) (CPMP/ICH/135/95), and the Principles of the ICH cGCP. The protocol 
will be submitted for approval to the EC/IRB, and written approval obtained before subjects are 
enrolled. The composition of the EC/IRB will also be provided to the Sponsor. If approval is 
suspended or terminated by the IRB, the PI will notify the Sponsor immediately 
Where applicable, the clinical site and Arrowhead Pharmaceuticals, Inc. agree to abide by the local 
compensation guidelines for injury resulting from participating in a company-sponsored research 
project. Compensation will only be provided on the understanding that the provision of 
compensation does not amount to an admission of legal liability and is subject to the proposed 
recipient signing a full and complete release of the company from all claims, damages and costs. 
13.4. Written Informed Consent 
Informed consent will be obtained before the patient can participate in the study. The contents 
and process of obtaining informed consent will be in accordance with all applicable regulatory 
requirements. Study participation includes all screening procedures, as well as any wash-out of 
excluded medications. 
It is the responsibility of the PI (or medically qualified designee) to obtain a written informed 
consent from everyone participating in this study after adequate explanation of the aims, 
methods, objectives, and potential hazards of the study. The PI (or medically qualified 
designee) must also explain to the participants that they are completely free to refuse to enter 
the study or to withdraw from it at any time. Appropriate forms for documenting a written 
consent will be provided by the PI or by Arrowhead Pharmaceuticals, Inc. 
For this study, each eligible participant will be required to provide written informed consent 
before participation in the study. 
All eligible participants will have the study explained by the PI or designee. They will receive a 
full explanation, in lay terms, of the aims of the study, the discomforts, risks and benefits in taking 
part as well as of insurance and other procedures for compensation in case of injury. It will be 
explained that the study is for research purposes only and is not expected to provide any 
therapeutic benefit to the individual. It will be pointed out that they can withdraw from the study at 
any time without prejudice. Each participant will acknowledge receipt of this information by 
giving written informed consent for participation in the study. The volunteer will be given a copy 
of the signed Informed Consent Form to retain. 
13.5. Emergency Contact with Principal Investigator 
Suitable arrangements will be made for participants to contact the PI or medically trained 
designee in the event of an emergency. 
 
 

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13.6. Notification of General Practitioner 
It is the responsibility of the PI or designee, to notify, where applicable, with the consent of the 
participant, the general practitioner of the patient’s participation in the trial, by sending a letter 
stating the nature of the trial, treatments, expected benefits or adverse events and concomitant 
drugs to be avoided. 
13.7. Clinical Laboratory Certification and Reference Ranges 
Before the initiation of this study, the PI, or designee, will obtain a copy of the certification form, 
with certification number and expiration date for all clinical laboratories (excluding central 
laboratories) used in the study. Reference ranges for each clinical laboratory test used in this study 
will be obtained from the appropriate laboratory, which will perform the test for the study. 
13.8. Protocol Deviations 
A protocol deviation is defined as any intentional or unintentional change to, or noncompliance 
with, the approved protocol procedures or requirements. The PI will conduct the study in 
compliance with the approved protocol and will not implement any deviation from or changes to 
the protocol without prior agreement by the Sponsor and review and documented approval from 
the EC/IRB of an amendment, except where necessary to eliminate an immediate hazard to study 
patients. 
Deviations may result from the action or inaction of the participant, PI, or site staff. Examples of 
deviations include, but are not limited to: 
• Failure to adhere to study exclusion and inclusion criteria 
• Failure to comply with dispensing or dosing requirements 
• Use of medications, food, drink, herbal remedies, or supplements that are specifically 
prohibited in the protocol 
• Missed or out-of-window visits 
• Drug dosing not administered within the time frame specified in the protocol 
• Failure to adhere to test requirements, including vital signs, laboratory tests, physical 
examinations, PK blood draws, medical history, etc. – either tests not done, incorrect tests 
done, or not done within the time frame specified in the protocol 
Protocol deviations impacting patient safety or eligibility will be reported to the Sponsor or CRO 
within 2 business days of occurrence and to the EC/IRB /competent regulatory authority per local 
regulatory requirements. 
 
The PI is responsible for ensuring that any known protocol deviations are recorded and reported 
as agreed. 
 
13.9. Termination of the Study 
The Sponsor reserves the right to discontinue the trial at any time. Reasons will be provided in 
the event of this happening. The PI reserves the right to discontinue the study for safety reasons at 
any time in collaboration with the Sponsor. 
 
 

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14. 
STUDY ADMINISTRATION  
14.1. Study Monitoring 
Arrowhead Pharmaceuticals, Inc. is responsible for assuring the proper conduct of the study 
about protocol adherence and validity of the data recorded on the eCRFs. Participant 
confidentiality will be maintained. 
In accordance with applicable regulations, cGCP, and Arrowhead Pharmaceuticals, Inc. 
procedures, Arrowhead Pharmaceuticals, Inc. will be responsible for assigning a study monitor 
(CRA) who will contact the site to organize a visit prior to participant enrolment to review the 
protocol and data collection procedures with site staff. In addition, the assigned study monitor 
will periodically contact the site, including conducting on-site visits. The extent, nature and 
frequency of on-site visits will be based on such considerations as the study objective and/or 
endpoints, the purpose of the study, study design complexity, and enrolment rate. 
During these site visits, the study monitor will: 
• Check the progress of the study 
• Review study data collected 
• Conduct source document verification 
• Identify any issues and address their resolution 
• Check investigational product accountability 
• Review blood and urine samples and ensure they are labeled and stored correctly  
This will be done to verify that the: 
• Data are authentic, accurate and complete. 
• Safety and rights of participants are being protected. 
• Study is conducted in accordance with the currently approved protocol (and any amendments), 
cGCP and all applicable regulatory requirements. 
The PI agrees to allow the monitor direct access to all relevant documents and to allocate his/her 
time and the time of his/her staff to the monitor to discuss findings and any relevant issues. 
At study closure, a study monitor will conduct the following activities in conjunction with the PI 
or site staff as appropriate: 
• Return of all study data to Arrowhead Pharmaceuticals, Inc 
• Data queries 
• Accountability, reconciliation and arrangements for unused investigational product(s) 
• Inventory and final disposition (e.g., destruction, shipping to repository, etc.) 
• Review of site study records for completeness 
14.2. Quality Assurance 
To ensure compliance with cGCP and all applicable regulatory requirements, Arrowhead 
Pharmaceuticals, Inc. may conduct a quality assurance audit of the study site. Regulatory agencies 
may also conduct a regulatory inspection of this study. Such audits/inspections can occur at any 
time during or after completion of the study. If an audit or inspection occurs, the PI and clinical 
site agree to notify Sponsor as soon as possible following awareness of an impending regulatory 
inspection. The PI and clinical site agree to allow the auditor/inspector direct access to all relevant 
documents and allocate his/her time and the time of his/her staff to the auditor/inspector to discuss 
findings and any relevant issues. 

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• Change in sinus discharge 
• Change in physical examination (PE) of the chest 
• Decrease in pulmonary function by 10% 
• Radiographic changes indicative of pulmonary infection 
• Increased respiratory rate or dyspnea at rest 
16.2. Guideline for Evaluation and Treatment of Hyperkalemia for NHVs and CF 
Patients 
Hyperkalemia related to renal ENaC inhibition is not expected in this clinical study. However, as a 
precaution, the following guideline (derived from D B Mount et al., Treatment and Prevention of 
Hyperkalemia in adults, UpToDate, 2020), is provided to monitor and treat patients with treatment 
emergent hyperkalemia. 
1. Any otherwise unexplained (e.g. no hemolysis) hyperkalemia (K+ > ULN per central lab 
reference range) will result in: 
a. Immediate return to clinic or local healthcare provider for repeat K+ and ECG. 
Confirmed hyperkalemia will further result in: 
i. 
Patients with K+ > 6.5 mmol/L or with any symptoms of muscle weakness or paralysis 
or new clinically significant cardiac conduction abnormalities on ECG consistent with 
hyperkalemia (as compared to pre-dose ECG) should result in treatment with 
therapies to stabilize myocardium, and remove potassium from circulation 
(intravenous calcium in addition to intravenous insulin and dextrose). Also consider 
use of diuretics and/or cation exchangers and possibly hospital admission. 
ii. If potassium is > ULN but < 6.5 mmol/L in the absence of symptoms or ECG findings, 
treatment for elevated potassium may include only diuretics or cation exchangers. 
Consider hospital admission. 
iii. Patient should be followed at least weekly until K+ < ULN. 
iv. Confirmed elevated potassium will result in discontinuation of dosing in the individual 
patient. 
Local labs may be utilized as necessary (including for Screening) if needed by the investigator or 
for emergent situations, including time critical analytes such as serum potassium and repeat 
clinical chemistries. 

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