A Phase 1, Randomized, Double-blind, Placebo-controlled, Safety, Tolerability, and Pharmacokinetic Study of Single Ascending Doses and Multiple Doses of WVE-006 in Healthy Participants
Phase: PHASE1
Conditions: Alpha-1 Antitrypsin Deficiency (AATD)
Sponsor: Wave Life Sciences Ltd.

 
 
 
PROTOCOL TITLE: 
A Phase 1, Randomized, Double-blind, Placebo- 
controlled, Safety, Tolerability, and Pharmacokinetic 
Study of Single Ascending Doses and Multiple Doses 
of WVE-006 in Healthy Participants 
PROTOCOL NUMBER 
WVE-006-001 
IRAS ID NUMBER 
1008635 
AMEDENDMENT NUMBER 
Initial 
DATE 
29 August 2023 
COMPOUND 
WVE-006 
BRIEF TITLE 
A Phase 1, Randomized, Double-Blind, Placebo- 
Controlled Study in Healthy Participants 
STUDY PHASE 
Phase 1 
SPONSOR NAME/ 
LEGAL REGISTERED 
ADDRESS: 
Wave Life Sciences UK Limited 
1 Chamberlain Square CS 
Birmingham, B3 3AX 
United Kingdom 
CONFIDENTIAL INFORMATION 
This document is the sole property of Wave Life Sciences. This document and any and all 
information contained herein has to be considered and treated as strictly confidential. This 
document will be used only for the purpose of the disclosure herein provided. No disclosure or 
publication will be made without the prior written consent of Wave Life Sciences. 

PRINCIPAL INVESTIGATOR’S AGREEMENT 
 
I have read and understand the contents of this clinical protocol for Protocol No. WVE-006-001 
dated 29 August 2023 and will adhere to the study requirements as presented, including all 
statements regarding confidentiality. In addition, I will conduct the Study in accordance with 
current International Conference on Harmonization guidelines governing Good Clinical 
Practices, applicable US Food and Drug Administration (USFDA) regulations, and other local 
regulatory requirements: 
Name of Principal Investigator: 
 
Title: 
 
 
 
Institution: 
 
 
 
Address: 
 
 
 
 
 
Phone: 
 
 
Fax: 
 
 
 
 
 
 
 
 
 
Signature 
 
Date 

TABLE OF CONTENTS 
 
Clinical Protocol Approval Form ..................................................................................... 2 
Principal Investigator’s Agreement .................................................................................. 3 
Table of Contents ............................................................................................................... 4 
List of Tables ...................................................................................................................... 6 
List of Figures ..................................................................................................................... 6 
List of Abbreviations .......................................................................................................... 7 
1 
Protocol Summary .................................................................................................... 10 
1.1 
Protocol Synopsis.................................................................................................. 10 
1.2 
Protocol Schema ................................................................................................... 18 
1.3 
Schedule of Assessments ...................................................................................... 19 
2 
Introduction ............................................................................................................... 28 
2.1 
Study Rationale .................................................................................................... 28 
2.2 
Background ........................................................................................................... 28 
2.3 
Benefit/Risk Assessment ...................................................................................... 28 
2.3.1 
Risk Assessment.............................................................................................. 29 
2.3.2 
Benefit Assessment ......................................................................................... 30 
2.3.3 
Overall Benefit-Risk Conclusions ................................................................. 30 
3 
Objectives, EndPoints, and Estimands ................................................................... 31 
4 
Study Design .............................................................................................................. 32 
4.1 
Overall Study Design ........................................................................................... 32 
4.1.1 
Screening ......................................................................................................... 33 
4.1.2 
Treatment ........................................................................................................ 33 
4.1.3 
Follow-up ......................................................................................................... 34 
4.1.4 
Early Termination .......................................................................................... 35 
4.2 
Scientific Rationale for Study Design ................................................................. 35 
4.3 
Justification for Dose ........................................................................................... 35 
4.4 
End of Study Definition ....................................................................................... 36 
5 
Study Population ....................................................................................................... 37 
5.1 
Inclusion Criteria ................................................................................................. 37 
5.2 
Exclusion Criteria ................................................................................................ 38 
5.3 
Screen Failures ..................................................................................................... 40 
6 
Study Drugs and Concomitant Therapy ................................................................. 41 
6.1 
Study Drugs Administered .................................................................................. 41 
6.2 
Preparation, Handling, Storage, and Accountability ........................................ 42 
6.3 
Study Drug Administration ................................................................................. 42 
6.4 
Assignment to Study Drug ................................................................................... 43 
6.5 
Blinding ................................................................................................................. 43 
6.5.1 
Breaking the Blind ......................................................................................... 43 
6.6 
Study Drug Compliance ....................................................................................... 44 
6.7 
Dose Modification ................................................................................................. 44 
6.8 
Continued Access to Study Drug after the End of the Study ........................... 44 
6.9 
Treatment of Overdose ........................................................................................ 44 
6.10 
Prior and Concomitant Therapy......................................................................... 45 
7 
Discontinuation of Study Drug and Participant Discontinuation/Withdrawal ... 46 
7.1 
Discontinuation of Study Treatment in Period 2 ............................................... 46 

TABLE OF CONTENTS 
 
7.1.1 
Period 2 Individual Stopping Criteria .......................................................... 46 
7.1.2 
Withdrawal of Participants from the Study ................................................ 46 
7.2 
Dose Interruption ................................................................................................. 47 
7.3 
Lost to Follow-up .................................................................................................. 47 
7.4 
Replacements ........................................................................................................ 47 
8 
Study Assessments and Procedures ......................................................................... 49 
8.1 
General Baseline and Administrative Assessments ........................................... 49 
8.1.1 
Medical History and Demographics ............................................................. 49 
8.1.2 
Height and Weight ......................................................................................... 49 
8.1.3 
Eligibility Criteria Review ............................................................................. 49 
8.1.4 
Drug, Alcohol, and Cotinine Screening ........................................................ 49 
8.1.5 
Follicle Stimulating Hormone ....................................................................... 50 
8.1.6 
Viral Serology ................................................................................................. 50 
8.1.7 
COVID-19 Testing ......................................................................................... 50 
8.2 
Efficacy Assessments ............................................................................................ 50 
8.3 
Safety Assessments ............................................................................................... 50 
8.3.1 
Prior and Concomitant Medications ............................................................ 51 
8.3.2 
Physical Examination ..................................................................................... 51 
8.3.3 
Vital Signs (Blood Pressure, Heart Rate and Temperature) ...................... 51 
8.3.4 
Digital Continuous and Triplicate 12-Lead ECG ........................................ 51 
8.3.5 
Clinical Laboratory Evaluations ................................................................... 51 
8.3.6 
Pregnancy Testing .......................................................................................... 52 
8.4 
Adverse Events ..................................................................................................... 52 
8.5 
Pharmacokinetic Assessments ............................................................................. 52 
8.6 
Pharmacodynamic Assessments .......................................................................... 53 
8.7 
Genetics ................................................................................................................. 54 
8.8 
Biomarkers ............................................................................................................ 54 
8.9 
Immunogenicity Assessments .............................................................................. 54 
8.10 
Health Economics ................................................................................................. 54 
9 
Statistical Considerations ......................................................................................... 55 
9.1 
Sample Size Determination .................................................................................. 55 
9.2 
Analysis Populations ............................................................................................ 55 
9.3 
Statistical Analyses ............................................................................................... 55 
9.3.1 
General Considerations ................................................................................. 55 
9.3.2 
Disposition of Participants ............................................................................. 56 
9.3.3 
Participants’ Demographics and Baseline Characteristics ......................... 56 
9.3.4 
Study Drug Exposure and Compliance ........................................................ 56 
9.3.5 
Analysis of Safety Data .................................................................................. 56 
9.3.6 
Pharmacokinetic Analysis ............................................................................. 57 
9.3.7 
Interim Analyses ............................................................................................. 58 
10 Supporting Documentation and Operational Considerations ............................... 59 
10.1 
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations ......... 59 
10.1.1 
Regulatory and Ethical Considerations ........................................................ 59 
10.1.2 
Financial Disclosure ....................................................................................... 59 
10.1.3 
Informed Consent Process ............................................................................. 60 
10.1.4 
Privacy and Data Protection ......................................................................... 61 

TABLE OF CONTENTS 
 
10.1.5 
Committees Structure ....................................................................................61 
10.1.6 
Dissemination of Clinical Study Data ...........................................................62 
10.1.7 
Data Quality Assurance .................................................................................62 
10.1.8 
Source Documents ..........................................................................................63 
10.1.9 
Study and Site Start and Closure..................................................................63 
10.1.10 
Publication Policy ...........................................................................................64 
10.2 
Appendix 2: Clinical Laboratory Tests ..............................................................66 
10.3 
Appendix 3: AEs and SAEs: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting ...............................................................68 
10.3.1 
Eliciting and Documenting Adverse Events .................................................68 
10.3.2 
Time Period and Frequency for Collecting AE and SAE Information .....68 
10.3.3 
Follow-up of AEs and SAEs ..........................................................................69 
10.3.4 
Definitions of Adverse Event Severity and Relationship to Study Drug ...69 
10.3.5 
Serious Adverse Events ..................................................................................70 
10.3.6 
Pregnancies .....................................................................................................72 
10.4 
Appendix 4: Contraceptive and Barrier Guidance ...........................................74 
10.4.1 
Definitions .......................................................................................................74 
10.4.2 
Highly Effective Methods of Contraception .................................................74 
10.5 
Appendix 5: Management of Protocol Amendments and Deviations ..............75 
10.5.1 
Modification of the Protocol ..........................................................................75 
10.5.2 
Protocol Deviations ........................................................................................75 
10.6 
Appendix 6: Grading of Injection Site Reactions ..............................................76 
11 References ..................................................................................................................77 
 
LIST OF TABLES 
Table 1 
Overall Schedule of Assessments (Period 1) ................................................19 
Table 2 
Plasma PK and Selected Laboratory Time Points (Period 1) ....................22 
Table 3 
Urine PK Cumulative Collection Periods (Period 1) ..................................22 
Table 4 
Triplicate ECG Assessment Time Points (Period 1) ...................................23 
Table 5 
Overall Schedule of Assessments (Period 2) ................................................23 
Table 6 
Plasma PK and Selected Laboratory Time Points (Period 2) ....................26 
Table 7 
Triplicate ECG Assessment Time Points (Period 2) ...................................27 
Table 8 
Study Objectives and Endpoints for WVE-006-001 ....................................31 
Table 9 
Study Drugs Administered ............................................................................41 
Table 10 
Study Periods ............................................................................................41 
Table 11 
Detailed Clinical Laboratory Tests .........................................................66 
Table 12 
NCI-CTCAE General Grading Criteria ................................................69 
Table 13 
Guidelines for Determining the Relationship (if any) Between Adverse 
Event and the Study Drug ...................................................................................70 

WVE-006-001 
A Phase 1, Randomized, Double-Blind, Placebo-Controlled Study in Healthy Participants 
WVE-006 
Confidential 
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LIST OF ABBREVIATIONS 
 
Abbreviation or Acronym 
Definition 
AAT 
alpha-1 antitrypsin 
AATD 
alpha-1 antitrypsin deficiency 
Ae 
a measure of amount of drug excreted in the urine 
Ae% 
the percentage of the administered dose that is excreted in urine 
AE 
adverse event 
AIMer 
A-to-I editing oligonucleotide 
ALT 
alanine transaminase 
aPTT 
activated partial thromboplastin time 
AST 
aspartate transaminase 
AUC; AUC0-24hr; AUC0-48hr; 
AUClast; AUCinf, AUCext; 
AUCtau 
area under the curve; AUC from time 0 to 24 hours; AUC from time 0 to 
48 hours; AUC from time 0 to last measurable concentration; AUC from time 0 
to infinity, AUC extrapolated to infinity; AUC over a dosing interval 
BMI 
body mass index 
bpm 
beats per minute 
BUN 
blood urea nitrogen 
BSA 
body surface area 
CBC 
complete blood count 
CFR 
Code of Federal Regulations 
CIOMS 
Council for International Organizations of Medical Sciences 
CL 
clearance 
Cmax 
maximum (peak) concentration of drug 
COPD 
chronic obstructive pulmonary disease 
CRO 
contract research organization 
CRP 
C-reactive protein 
CRU 
clinical research unit 
CSR 
clinical study report 
CTCAE 
Common Terminology Criteria for Adverse Events 
cum Ae% 
cumulative Ae% 
CV% 
percent coefficient of variation 
DEC 
Dose Escalation Committee 
DMC 
Data Monitoring Committee 
EC 
ethics committee 

WVE-006-001 
A Phase 1, Randomized, Double-Blind, Placebo-Controlled Study in Healthy Participants 
WVE-006 
Confidential 
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Abbreviation or Acronym 
Definition 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EDC 
electronic data capture 
eGFR 
estimated glomerular filtration rate 
EMEA 
European Medicines Evaluation Agency 
ET 
early termination 
FIH 
first-in-human 
FSH 
follicle stimulating hormone 
GalNAc 
N-acetylgalactosamine 
GCP 
Good Clinical Practice 
GLDH 
glutamate dehydrogenase 
HBsAg 
hepatitis B surface antigen 
hCG 
human chorionic gonadotropin 
HED 
human equivalent dose 
HIV 
human immunodeficiency virus 
HRT 
hormone replacement therapy 
HV 
healthy volunteer 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
INR 
international normalized ratio 
IRB 
institutional review board 
IUD 
intrauterine device 
IUS 
intrauterine hormone-releasing system 
M-AAT 
M allele (wild type) version of AAT protein 
MCH 
mean corpuscular hemoglobin 
MCHC 
mean corpuscular hemoglobin concentration 
MCV 
mean corpuscular volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
mRNA 
messenger ribonucleic acid 
MTD 
maximum tolerated dose level 
NCI 
National Cancer Institute 
 
 
CC

WVE-006-001 
A Phase 1, Randomized, Double-Blind, Placebo-Controlled Study in Healthy Participants 
WVE-006 
Confidential 
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Abbreviation or Acronym 
Definition 
NOAEL 
no observed adverse effect level 
PD 
pharmacodynamic 
PK 
pharmacokinetic 
PT 
preferred term 
Q2W 
every other week 
QTcF 
QT interval corrected using Fridericia’s formula 
RBC 
red blood cell 
RNA 
ribonucleic acid 
SAD 
single ascending dose 
SAE 
serious adverse event 
SAR 
serious adverse reaction 
SC 
subcutaneous 
SD 
standard deviation 
SERPINA1 
Serpin Family A Member 1 
SoA 
schedule of assessments 
SOC 
system organ class 
SpO2 
percentage oxygen saturation in the blood 
SUSAR 
suspected unexpected serious adverse reaction 
t½ 
terminal elimination half-life 
TEAE 
treatment emergent adverse event 
tmax 
time to Cmax 
ULN 
upper limit of normal 
USFDA 
United States Food and Drug Administration 
Vd 
volume of distribution 
WBC 
white blood cell 
WOCBP 
women of childbearing potential 
Z-AAT 
Z allele (mutant) version of AAT protein 

WVE-006-001 
A Phase 1, Randomized, Double-Blind, Placebo-Controlled Study in Healthy Participants 
WVE-006 
Confidential 
Page 10 of 77 
 
 
 
1 PROTOCOL SUMMARY 
1.1 
Protocol Synopsis 
 
Sponsor: 
Wave Life Sciences UK 
Limited 
Investigational Product: 
WVE-006 
Developmental Phase: 
Phase 1 
IRAS ID Number: 
1008635 
Protocol Title: A Phase 1, Randomized, Double-blind, Placebo-controlled, Safety, Tolerability, and 
Pharmacokinetic Study of Single Ascending Doses and Multiple Doses of WVE-006 in Healthy 
Participants 
Protocol Number: WVE-006-001 
Brief Title: A Phase 1, Randomized, Double-blind, Placebo-controlled, Single Ascending Dose and 
Multiple-Dose Study of WVE-006 in Healthy Participants 
Pediatric Investigation Plan Number: Not applicable 
Rationale: 
Alpha-1 antitrypsin (AAT) is an acute phase protein predominantly produced by hepatocytes. Serum AAT 
protects the lung against proteolytic enzymes such as neutrophil elastase. Alpha-1 antitrypsin deficiency 
(AATD) is caused by mutations in the Serpin Family A Member 1 (SERPINA1) gene which follow an 
autosomal, codominant recessive inheritance pattern with a codominant genetic trait for AAT production. 95% 
of severe AATD cases are due to homozygous substitution of a single amino acid, Glu342Lys (protein inhibitor 
[PI]*ZZ). This produces a mutant (Z) misfolded and poorly secreted AAT protein (Z-AAT). The retention of 
misfolded Z-AAT protein in the liver causes proteotoxic stress leading to progressive gain of function liver 
disease from fibrosis to cirrhosis to risk of hepatocellular carcinoma. In contrast, the deficiency of AAT in 
serum leads to loss of function pulmonary disease which is manifested as chronic obstructive pulmonary disease 
(COPD), mostly emphysema and bronchiectasis. 
WVE-006 is an oligonucleotide that was designed to specifically edit the SERPINA1-Z messenger ribonucleic 
acid (mRNA) back to wildtype (M). Editing of the SERPINA1-Z mRNA back to wild type is expected to 
increase the concentration of M-AAT protein in the serum and decrease the accumulation of Z-AAT in the liver, 
thus addressing both the lung and liver disease manifestations associated with AATD. 
WVE-006 is not expected to have pharmacological activity in healthy volunteers (HV) as they do not have the 
mutation. 
Study Center(s): Up to 4 clinical research units 
Objectives and Endpoints: 
Objectives 
Endpoints 
Primary 
• 
To evaluate the safety and tolerability of 
WVE-006 
• 
Incidence of treatment emergent adverse events 
(TEAEs), related TEAE, severe TEAE, serious 
TEAE 
• 
Changes in safety assessment parameters (e.g., 
physical exam, vital signs, clinical laboratory 
results, electrocardiograms (ECGs) [including any 
changes to QTcF]) 

WVE-006-001 
A Phase 1, Randomized, Double-Blind, Placebo-Controlled Study in Healthy Participants 
WVE-006 
Confidential 
Page 11 of 77 
 
 
 
 
Sponsor: 
Wave Life Sciences UK 
Limited 
Investigational Product: 
WVE-006 
Developmental Phase: 
Phase 1 
IRAS ID Number: 
1008635 
• 
Tolerability based on incidence of discontinuation 
due to TEAEs 
Secondary 
• 
To evaluate the pharmacokinetics (PK) of 
WVE-006 after a single dose in healthy 
participants 
• 
To evaluate the PK of WVE-006 after multiple 
doses in healthy participants 
• 
PK parameters of WVE-006 in plasma, including 
AUCinf, AUC0-24h, AUC0-48h, AUClast, Cmax, tmax 
• 
PK parameters of WVE-006 in plasma following 
first and last doses, including AUCtau, AUC0-24h, 
AUC0-48h, AUClast, Cmax, tmax 
Exploratory 
• 
To evaluate urine excretion of WVE-006 
• 
Amount excreted (Ae), Ae% and cumulative Ae% 
(cum Ae%) for parent drug, as well as potential 
metabolites in urine 

WVE-006-001 
A Phase 1, Randomized, Double-Blind, Placebo-Controlled Study in Healthy Participants 
WVE-006 
Confidential 
Page 13 of 77 
 
 
 
 
Sponsor: 
Wave Life Sciences UK 
Limited 
Investigational Product: 
WVE-006 
Developmental Phase: 
Phase 1 
IRAS ID Number: 
1008635 
(1 active:1 placebo) during the multiple dose portion of the study. The sentinel participants will be dosed and 
monitored in the clinic for a minimum of 48 hours to identify any potential acute safety events. If neither of 
these sentinel participants experiences stopping criteria and if there are no other safety concerns during this 
48-hour period, the remaining 6 participants will be randomized in a blinded fashion to active study drug (n=5) 
or placebo (n=1) and may be dosed on the same day.WVE-006 or placebo will be administered every other week 
(Q2W) over 4 weeks (total of 3 doses; Weeks 0, 2, and 4). Following the first dose (Week 0) and last dose 
(Week 4), all participants will stay in the clinic for two nights for PK assessments. Following the second dose 
(Week 2), all participants will be observed for safety evaluation in the clinic for at least 4 hours post-study drug 
administration or per local SOP (whichever is longer). All participants will attend weekly follow-up clinic visits 
for safety, tolerability, and PK assessments through Week 12 followed by visits every 4 weeks through week 16 
or early termination visit. 
Dose Escalation Stopping Criteria (Period 1): 
Dose escalation will be paused until further evaluation by the DMC if any of the following criteria are met. If it 
is confirmed that a stopping criterion was met, no further dosing will take place until after submission and 
approval of a substantial amendment if the DMC recommends the trial can continue. 
• 
One or more participants experiencing at least possibly related Common Terminology Criteria for 
Adverse Events (CTCAE) Grade ≥3 TEAE or CTCAE grade ≥3 laboratory abnormality in a single 
cohort. 
o 
All grade 3 toxicities for vital signs must be confirmed with a repeat measurement obtained 
within 1 hour. 
o 
All grade 3 toxicities for laboratory parameters must be confirmed with a repeat measurement 
obtained within 24 hours. 
• 
Two or more participants experiencing at least possibly related CTCAE grade ≥2 TEAEs or CTCAE 
Grade ≥2 laboratory abnormalities in a single cohort. 
o 
All grade 2 toxicities for vital signs must be confirmed with a repeat measurement obtained 
within 1 hour. 
o 
All grade 2 toxicities for laboratory parameters must be confirmed with a repeat measurement 
obtained within 24 hours. 
• 
One or more participants experiencing any at least possibly related SAE in a single cohort. 
Period 2 Individual Stopping Criteria: 
Dosing will be paused or discontinued (per Investigator judgment) for an individual participant at any time in 
the study if: 
• 
Participant experiences any severe or serious adverse event considered at least possibly related to study 
drug. 
• 
Participant experiences, in the Investigator’s opinion, clinically significant hypersensitivity to 
WVE-006 (or placebo) administration. 
• 
Participant has any medical condition that is judged by the Investigator to jeopardize the participant’s 
safety if he or she continues to receive the study drug. 
On discontinuation of treatment, participants will be encouraged to continue follow-up for safety per protocol. 
Per Investigator judgment with consultation with the Sponsor, the participant may be allowed to resume 
participation in the study if/when the event has resolved. 

WVE-006-001 
A Phase 1, Randomized, Double-Blind, Placebo-Controlled Study in Healthy Participants 
WVE-006 
Confidential 
Page 14 of 77 
 
 
 
 
Sponsor: 
Wave Life Sciences UK 
Limited 
Investigational Product: 
WVE-006 
Developmental Phase: 
Phase 1 
IRAS ID Number: 
1008635 
Number of Participants (Planned): Up to 48 participants are planned to be enrolled; up to 40 participants in 
Period 1 (8 per each of the up to five planned SAD cohorts) and up to 8 new participants in the multidose 
Period 2. 
Should the DEC and DMC recommend to include an optional SAD cohort, an additional 8 participants will be 
enrolled for a total of up to 56 participants. Fewer than 48 participants may be enrolled if the DEC and DMC 
decide fewer cohorts are needed. 
Study Arms and Duration: 
Study arms in both Period 1 and Period 2 are up to 6 WVE-006 and up to 2 placebo treated participants 
(3:1 active:placebo) in each of the planned cohorts. 
Period 1 SAD: duration for each participant is expected to be up to 16 weeks: Screening of up to 28 days, 
followed by a single dose administration on Day 1, followed by safety, tolerability, and PK assessment through 
Day 85. 
Period 2 Multidose: duration for each participant is expected to be up to 20 weeks: Screening of up to 28 days, 
followed by 3 dose administrations on Weeks 0, 2, and 4, followed by safety, tolerability, and PK assessment 
through Day 113 Visit (i.e., Day 85 following last dose administration). 
Eligibility Criteria: 
Participants must meet all inclusion criteria and none of the exclusion criteria. For eligibility purposes, abnormal 
laboratory or vital signs or ECG results may be repeated once during the Screening period or Day -1 (as 
applicable) for confirmation if an abnormal result is observed at the initial assessment. 
Inclusion criteria 
1. Participant is capable of understanding and be willing to provide written informed consent prior to any 
study-related procedures. 
2. Participant is capable of understanding and adhering to all the requirements, procedures, instructions, and 
restrictions required by the protocol including scheduled visits, drug administration plan, laboratory tests, 
and likely to complete the study as planned. 
3. Healthy as determined by the Investigator, based on a medical evaluation, including medical history, 
concomitant medications, full physical examination, vital signs, laboratory tests, and ECGs at Screening 
and Day -1. Per Investigator’s judgement, there should be no evidence of cardiovascular, pulmonary, 
endocrine, hepatic, biliary, gastrointestinal, neurological, hematological, immunological, metabolic, 
skeletal, renal, psychiatric disorders, or cancer within the past 5 years prior to Screening visit (except 
localized or in situ cancer of the skin). Clinical abnormality or laboratory parameter(s) outside normal range 
must not be clinically significant or unlikely to introduce additional risk to the participant nor interfere with 
the study procedures nor the interpretation of any of the study assessments. 
4. Male or female healthy participants 18-65 years of age at Screening Visit. 
5. Participant has a body mass index (BMI) between 18 to 32 kg/m2 inclusive at Screening and Day -1 Visits. 
6. Genetic testing confirming PI*MM. 
7. Participant has been a non-smoker for at least 1 year prior to screening and agrees to abstain from tobacco 
and nicotine containing products for the duration of the study. 
8. Women of childbearing potential (WOCBP) must be: 
a) Non-pregnant as determined by a negative serum pregnancy test at Screening and negative highly 
sensitive urine pregnancy test on Day -1. 
b) Non lactating. 

WVE-006-001 
A Phase 1, Randomized, Double-Blind, Placebo-Controlled Study in Healthy Participants 
WVE-006 
Confidential 
Page 15 of 77 
 
 
 
 
Sponsor: 
Wave Life Sciences UK 
Limited 
Investigational Product: 
WVE-006 
Developmental Phase: 
Phase 1 
IRAS ID Number: 
1008635 
c) Agree to use a highly-effective method of contraception (as defined in Section 10.4) from 
 prior 
to Day 1 and for at least 
 following last study drug administration. Exception: Women 
exclusively engaging in same-sex sexual activities are not required to meet this criterion. 
d) Must be willing to forgo ova (egg) donation for at least 
 following the last study drug 
administration. 
9. Women of non-childbearing potential are defined as meeting at least 1 of the following criteria: 
a) At least 12 months post-menopausal and has an FSH >40 mIU/mL. 
b) Surgically sterile, defined as having a documented bilateral oophorectomy, or hysterectomy. 
10. Male participants must be willing to follow contraceptive requirements (as defined in Section 10.4) and 
should not impregnate anyone while they are in the study and for at least 
 following the last dose 
of study drug. In addition, participant must be willing to forgo sperm donation for at least 
 
following the last dose of study drug. Men exclusively engaging in same-sex sexual activities are not 
required to meet this criterion. 
Exclusion criteria 
1) Participant has a history of multiple drug allergies or of allergic reaction to an oligonucleotide or to 
N-acetylgalactosamine (GalNAc). 
2) Participant has a history of intolerance or any medical condition that might interfere with SC injection(s). 
3) History or signs or symptoms of severe (bacterial, viral, parasitic, or fungal) infection within 4 weeks prior 
to Screening or Day -1 Visits. 
4) History or signs or symptoms of an acute illness (including COVID-19) within 10 days prior to dosing on 
Day 1 Visit. Exception: mild seasonal allergies. 
5) Positive COVID-19 test, if applicable per site SOP, at Screening and Day -1 Visit. 
6) Participant received a COVID-19 or any other vaccine within 14 days before dosing on Day 1 Visit or is 
scheduled for vaccination anytime during the study. 
7) Participant has total bilirubin > upper limit of normal (ULN) though participants with documented Gilbert’s 
syndrome with normal conjugated bilirubin are eligible; aspartate transaminase (AST) and/or alanine 
transaminase (ALT) >ULN at Screening and Day -1. 
8) Participant has estimated glomerular filtration rate (eGFR) ≤60 ml/min/1.73mm2 (calculated by the 
Cockcroft-Gault formula) at Screening and Day -1. 
9) Participant has a positive serology for hepatitis B or hepatitis C at Screening; participants with positive 
hepatitis B serology may be enrolled if there is evidence the participant received HBV immunization. 
10) Participant is known to be positive for human immunodeficiency virus (HIV) and/or positive serology for 
HIV 1/2 where testing is permitted per local regulations. 
11) Participant has a history of regular alcohol consumption exceeding 14 standard drinks/week. 1 standard 
drink is equivalent to 14g ethanol or 5 US fluid ounces (fl oz) (150 mL) of wine (approximately 
12% alcohol by volume), 12 fl oz (360 mL) of beer (approximately 5% alcohol by volume), or 1.5 fl oz 
(45 mL) of hard liquor (approximately 40% alcohol by volume), within 1 year prior to the Screening Visit. 
12) Participant has a history of caffeine consumption exceeding 8 cups of coffee/day (1 cup = 8 fl oz [240mL]) 
within 14 days prior to first study dose, or consumption of any caffeine or chocolate containing products for 
3 days prior to clinical research unit admission. Caffeine-containing food and/or beverages (e.g., tea, cola) 
should be considered equivalent to coffee. 
13) Unwilling to abstain from alcohol for 48 hours prior to dosing at each of the dosing visits. 
14) Participant has a positive alcohol test at Screening and/or Day -1 Visits. 
CCI
CCI
CCI
CCI
CCI

WVE-006-001 
A Phase 1, Randomized, Double-Blind, Placebo-Controlled Study in Healthy Participants 
WVE-006 
Confidential 
Page 16 of 77 
 
 
 
 
Sponsor: 
Wave Life Sciences UK 
Limited 
Investigational Product: 
WVE-006 
Developmental Phase: 
Phase 1 
IRAS ID Number: 
1008635 
15) Any prescribed or recreational substance use (irrespective of legality) within 6 months prior to screening or 
unwilling to refrain from such use for the duration of the study. 
16) Positive drug screen at Screening and/or Day -1 Visits. 
17) Positive cotinine test at Screening and/or Day -1 Visits. 
18) Use of prescription or non-prescription medications, including vitamin, dietary, and herbal supplements 
(including St John’s Wort) within 7 days or 5 half-lives (whichever is longer) prior to the first dose of study 
treatment unless, in the opinion of the Investigator and Sponsor, the medication will not interfere with 
interpretation of study assessments. Contraception and hormone replacement therapy (HRT) are permitted. 
If needed, over-the-counter (OTC) medications such as paracetamol/acetaminophen may be used acutely. 
19) History of major surgery in the 3 months prior to Screening Visit and/or planned surgery for the duration of 
the study. 
20) Sustained hypertension defined as at least 2 repeated measurements at least 15 minutes apart of systolic 
pressure exceeding 130 mm Hg and/or diastolic pressure exceeding 80 mm Hg at Screening and/or Day -1 
Visits. 
21) Supine pulse rate <45 beats per minute (bpm) or >100 bpm at Screening and/or Day -1 Visits. 
22) One or more of the following abnormal ECG findings at Screening and/or Day -1 Visits: 
a) Second- or third-degree atrioventricular block 
b) QRS >120 msec 
c) QTcF >450 msec for males or >470 msec for females 
d) PR interval >200 msec 
e) Any rhythm other than sinus rhythm that is considered clinically significant by the Investigator. 
23) History of risk factors for Torsade de Pointes including unexplained syncope, known long QT syndrome, 
heart failure, myocardial infarction, angina, or clinically significant abnormal laboratory assessments 
including hypokalemia, hypercalcemia, or hypomagnesemia. 
24) Family history of long QT syndrome or Brugada syndrome. 
25) Donation of blood or blood products in excess of 500 mL within 12 weeks prior to Screening Visit and/or 
unwilling to refrain from blood donation for the duration of the study. 
26) Participant has any medical or social condition which in the opinion of the Investigator, would make the 
participant unsuitable for participation in the study, for study treatment, or could interfere with the 
assessments of safety or PK, or completion of the study. 
27) Participant has received an investigational agent within 3 months or 5 half-lives (if known), or twice the 
duration of biological effect (if known), whichever is longer, before Screening, or who is in follow-up of 
another clinical study of an investigational agent at the time of the Screening Visit. 
28) Exposure to more than 4 new chemical entities within 12 months prior to the Day 1 Visit. 
29) Prior treatment with any oligonucleotide or small interfering RNA within 12 months prior to the Day 1 
Visit. 
30) Participant is directly or indirectly involved in the conduct and administration of this trial as an Investigator, 
sub-investigator, trial coordinator, or other trial staff member, or the participant is a first-degree family 
member, significant other, or relative residing with one of the above persons involved directly or indirectly 
in the trial. 
Blinding: The roles indicated below will not be made aware of the treatment group assignment during the study: 
• 
Participants 

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Sponsor: 
Wave Life Sciences UK 
Limited 
Investigational Product: 
WVE-006 
Developmental Phase: 
Phase 1 
IRAS ID Number: 
1008635 
• 
Trial staff members (excluding pharmacy staff) 
• 
Investigator 
• 
DEC 
• 
Sponsor, with certain documented exceptions as per DEC Charter 
Data Monitoring/Other Committee: Because the Investigator is part of DEC and must remain blinded for long 
term safety evaluation, an independent unblinded DMC will review available data on PK and safety prior to 
dose escalation at each cohort. 
Statistical Methods: 
The sample size was not calculated on the basis of statistical hypothesis testing; however, the number of 
participants is considered sufficient for a Phase 1 assessment of safety, tolerability, and PK. 
Treatment-emergent AEs overall and assessed as related to study drug or to study procedures, and treatment 
emergent SAEs, will be summarized for each dose group based on MedDRA coding of verbatim terms reported 
by Investigators. These summaries will be presented separately for Period 1 and Period 2. 
Pharmacokinetic parameters for WVE-006 will be calculated using non-compartmental methods. PK parameters 
will be summarized by treatment using descriptive statistics: n, arithmetic mean, median, standard deviation 
(SD), minimum, maximum, and percent coefficient of variation (CV%); in addition, the geometric mean and 
geometric CV% will be reported for Cmax and AUCs. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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1.3 
Schedule of Assessments 
Table 1 
Overall Schedule of Assessments (Period 1) 
 
Screening 
Perioda 
Dosing- CRU Stay 
Follow-up 
ET 
Visit 
1 
2 
3, 4, 5, 7, 8, 9, 11, 12, 13 
6 
10 
14 
Study Week 
Week -4 to 
Week 0 
Week 0 
Week 1, 2, 3, 5, 6, 7, 9, 
10, 11 
Week 
4 
Week 
8 
Week 
12 
Study Day 
Event/Assessment 
Day -28 to 
Day -2 
Day -1 
Day 1 
Day 2 
Day 3 
Day 8, 15, 22, 36, 43, 
50, 64, 71, 78 
(±3 days) 
Day 29 
(±3 days) 
Day 57 
(±3 days) 
Day 85 
(±5 days) 
Informed Consent 
X 
Demographics 
X 
Medical History 
X 
Prior/concomitant 
medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Admission to CRU 
X 
Discharge from CRU 
X 
Eligibility 
Criteria/Recheck 
X 
X 
AAT Genetic Testing 
X 
Serum Pregnancy Testb 
X 
X 
X 
Urine Pregnancy Testb 
X 
X 
X 
X 
X 
FSHc 
X 
Viral Serology 
X 
COVID-19 Testingd 
X 
X 

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Screening 
Perioda 
Dosing- CRU Stay 
Follow-up 
ET 
Visit 
1 
2 
3, 4, 5, 7, 8, 9, 11, 12, 13 
6 
10 
14 
Study Week 
Week -4 to 
Week 0 
Week 0 
Week 1, 2, 3, 5, 6, 7, 9, 
10, 11 
Week 
4 
Week 
8 
Week 
12 
Study Day 
Event/Assessment 
Day -28 to 
Day -2 
Day -1 
Day 1 
Day 2 
Day 3 
Day 8, 15, 22, 36, 43, 
50, 64, 71, 78 
(±3 days) 
Day 29 
(±3 days) 
Day 57 
(±3 days) 
Day 85 
(±5 days) 
Safety Laboratorye 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Plasma PK and Select 
Labs f 
X 
X 
X 
X 
X 
X 
X 
X 
Urine PK samplef 
X 
X 
X 
X 
X 
X 
X 
X 
Serum Sample for 
Immunogenicity 
X 
X 
X 
X 
X 
Full Physical Examg 
X 
X 
X 
X 
X 
X 
X 
Symptom-directed 
Physical Examg 
X 
X 
X 
Body Weight/BMIh 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Height 
X 
Vital Signsi 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Digital Continuous and 
Triplicate 12-lead ECGj 
X 
X 
X 
X 
X 
X 
Urine Drug Screenk; 
Cotinine; Alcohol Breath 
or Urine Test 
X 
X 
X 
X 
X 
X 
X 
Study Drug 
Administration SC 
Injection 
X 

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Screening 
Perioda 
Dosing- CRU Stay 
Follow-up 
ET 
Visit 
1 
2 
3, 4, 5, 7, 8, 9, 11, 12, 13 
6 
10 
14 
Study Week 
Week -4 to 
Week 0 
Week 0 
Week 1, 2, 3, 5, 6, 7, 9, 
10, 11 
Week 
4 
Week 
8 
Week 
12 
Study Day 
Event/Assessment 
Day -28 to 
Day -2 
Day -1 
Day 1 
Day 2 
Day 3 
Day 8, 15, 22, 36, 43, 
50, 64, 71, 78 
(±3 days) 
Day 29 
(±3 days) 
Day 57 
(±3 days) 
Day 85 
(±5 days) 
Adverse Event 
Monitoring 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Abbreviations: AAT = alpha-1 antitrypsin; BMI = body mass index; CRU = clinical research unit; ECG = electrocardiogram; ET = early termination; FSH = follicle 
stimulating hormone; PK = pharmacokinetic; SC = subcutaneous. 
a  Screening assessments can occur on multiple days, provided they are within the Day -28 up to Day -2 Screening period. 
b  Negative serum pregnancy test at Screening for women of childbearing potential (WOCBP). Negative highly sensitive urine pregnancy test documented for WOCBP on Day -1. 
c  FSH only to confirm non-childbearing potential. 
d  COVID-19 testing if required per site SOPs. 
e  Safety laboratory tests include hematology, clinical chemistry, coagulation and urinalysis as noted in Table 11. Note that for urinalysis, abnormal results on dipstick or 
urinalysis should lead to laboratory urinalysis testing and/or urine microscopy. Any specific safety labs indicated in Table 2 will be collected according to the schedule in that 
table. When applicable and feasible, blood sampling should follow evaluations of vital signs and ECGs to reduce any impact on these measurements. 
f  Specific time points for PK and select laboratory assessments provided in Table 2 and Table 3. Participants should stay in the clinic for 48 hours after dose to complete 
assessments. 
g Full physical examination includes (at a minimum): alertness and orientation, general appearance, skin, head, eyes, ears, nose, throat, lungs, cardiovascular, gastrointestinal, 
musculoskeletal, and neurologic systems. Symptom-directed physical exams to be performed by visit as necessary. 
h  Height at Screening will be used for BMI calculations at all visits. 
i  Vital signs will be taken with the participant in the supine position after ≥5 minutes of rest. Temperature, respiratory rate, and percent oxygen saturation in the blood (SpO2) are 
measured once per time point. Blood pressure (systolic and diastolic) and pulse: measured ≤30 minutes pre-dose and 1 hr (±10 min), 2 hr (±10 min), 4 hr (±20 min), 12 hr (±1 
hr) post dose on Day 1 and once at all other noted visits. 
j  Continuous digital ECG monitoring for at least 48 hours from Day -1 through Day 2; leads may be disconnected for ~20 minutes at 24 hours after dosing to allow for participant 
cleansing. Additional triplicate 12-lead ECGs are specified in Table 4. Participant must rest quietly for ≥5 minutes prior to triplicate ECGs. 
k  For drug screen panel, see Table 11 other screening tests. 

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Table 2 
Plasma PK and Selected Laboratory Time Points (Period 1) 
 
Visit 
2 
3 
4 
5 through 14 
Study Day/ 
Specific 
Time/ 
Window 
Day 1 
Day 2 
Day 3 
Day 8 
Day 15 
Weeks 3 through 12 
Pre- 
dose 
Post dose 
≤30 
min 
prior 
to 
doseb 
30 
min 
(±5 
min) 
1 hr 
(±5 
min) 
2 hr 
(±5 
min) 
4 hr 
(±10 
min) 
6 hr 
(±10 
min) 
8 hr 
(±10 
min) 
12 hr 
(±10 
min) 
24 hr 
(±30 
min) 
36 hr 
(±4 
hr) 
48 hr 
(±4 hr) 
(±3 
days) 
(±3 
days) 
(± 3 days) 
Plasma PKa 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Every week 
CBC, CRP, 
fibrinogen, 
coagulation, 
albumin 
X 
 
X 
X 
X 
X 
X 
Every week 
Complement 
X 
X 
X 
X 
X 
X 
X 
X 
Week 4 only 
Cytokinesc 
X 
X 
X 
X 
X 
X 
X 
X 
Week 4 only 
Abbreviations: CBC = complete blood count; CRP = C-reactive protein; PK = pharmacokinetic. 
a Sufficient plasma PK sample volume to cover both WVE-006 and potential metabolites. When applicable and feasible, PK blood sampling should follow evaluations of vital 
signs and ECGs to reduce any impact on these measurements. 
b Pre-dose laboratory results are NOT required prior to dosing. 
c Cytokine samples will be collected and may be analyzed for the following cytokines: IL-1β, IL-6, IL-10, IL-12/23 (P40), IFN-γ, TNF-α, MCP-1, and MIP-1β 
 
Table 3 
Urine PK Cumulative Collection Periods (Period 1) 
 
Study Day/ 
Time Frame 
Day 1 
Day 2 
Day 3 
0-4 hr 
4-8 hr 
8-12 hr 
12-18 hr 
18-24 hr 
24-36 hr 
36-48 hr 
Urine PKa 
X 
X 
X 
X 
X 
X 
X 
Abbreviation: PK = pharmacokinetic. 
a Urine for PK assessments will be collected continuously through 48 hours per the stated time periods. For each of these time periods, total volume will be captured in the 
electronic case report form (eCRF). 

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Table 4 
Triplicate ECG Assessment Time Points (Period 1) 
 
Study Day/ 
Specific 
Time 
Day 1 
Day 2 
Day 3 
Pre-dose 
Post dose 
-45 min 
±5 min 
-30 min 
±5 min 
-15 min 
±5 min 
30 min 
±5 min 
1 hr 
±5 min 
2 hr 
±5 min 
4hr 
±10 min 
6hr 
±10 min 
8hr 
±10 min 
12hr 
±10 min 
24hr 
±30 min 
48hr 
±4 hr 
ECGa 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Abbreviations: ECG = electrocardiogram 
a Digital ECG monitoring for at least 48 hours from Day -1 through Day 2. Additional triplicate ECG measurements at the time points listed here. 
 
Table 5 
Overall Schedule of Assessments (Period 2) 
 
Screening 
Perioda 
Treatment Period 
Follow-up Visit 
ET 
Visit 
1 
2 
4 
6 
3, 5, 7,8, 9, 
11, 12, 13, 
14, 15, 16 
10 
14 
15 
Study Week 
Week -4 
to 
Week 0 
Week 0 
CRU Stay 
Week 
2 
Week 4 
CRU Stay 
Week 1,3, 
5, 6, 7, 9, 
10, 11 
Week 
8 
Week 
12 
Week 
16 
Study Day/ 
Event/ 
Assessment 
Day -28 
to Day -2 
Day 
-1 
Day 
1 
Day 
2 
Day 
3 
Day 
15 
(±3 
days) 
Day 
29 
(±3 
days) 
Day 
30 
(±3 
days) 
Day 
31 
(±3 
days) 
Day 8, 21, 
36, 43, 50, 
64, 71, 78 
(±3 days) 
Day 
57 
(±3 
days) 
Day 
85 
(±3 
days) 
Day 
113 
(±5 
days) 
Informed Consent 
X 
 
Demographics 
X 
 
Medical History 
X 
 
Prior/concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Admission to CRU 
X 
 
Xb 
Xb 
Discharge from CRU 
 
X 
X 
X 

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Screening 
Perioda 
Treatment Period 
Follow-up Visit 
ET 
Visit 
1 
2 
4 
6 
3, 5, 7,8, 9, 
11, 12, 13, 
14, 15, 16 
10 
14 
15 
Study Week 
Week -4 
to 
Week 0 
Week 0 
CRU Stay 
Week 
2 
Week 4 
CRU Stay 
Week 1,3, 
5, 6, 7, 9, 
10, 11 
Week 
8 
Week 
12 
Week 
16 
Study Day/ 
Event/ 
Assessment 
Day -28 
to Day -2 
Day 
-1 
Day 
1 
Day 
2 
Day 
3 
Day 
15 
(±3 
days) 
Day 
29 
(±3 
days) 
Day 
30 
(±3 
days) 
Day 
31 
(±3 
days) 
Day 8, 21, 
36, 43, 50, 
64, 71, 78 
(±3 days) 
Day 
57 
(±3 
days) 
Day 
85 
(±3 
days) 
Day 
113 
(±5 
days) 
Eligibility criteria/Recheck 
X 
X 
 
AAT genetic testing 
X 
 
Serum Pregnancy Testc 
X 
 
X 
X 
Urine Pregnancy Testc 
X 
 
X 
X 
X 
X 
X 
X 
X 
FSHd 
X 
 
Viral Serology 
X 
 
COVID-19 testinge 
X 
X 
 
Safety Laboratoryf 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Plasma PK and Select Labsg 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serum sample for 
immunogenicity 
X 
 
X 
X 
X 
X 
X 
Full Physical Examh 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Symptom directed Physical 
Examh 
X 
X 
X 
X 
Body Weight/BMIi 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Height 
X 
 

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Screening 
Perioda 
Treatment Period 
Follow-up Visit 
ET 
Visit 
1 
2 
4 
6 
3, 5, 7,8, 9, 
11, 12, 13, 
14, 15, 16 
10 
14 
15 
Study Week 
Week -4 
to 
Week 0 
Week 0 
CRU Stay 
Week 
2 
Week 4 
CRU Stay 
Week 1,3, 
5, 6, 7, 9, 
10, 11 
Week 
8 
Week 
12 
Week 
16 
Study Day/ 
Event/ 
Assessment 
Day -28 
to Day -2 
Day 
-1 
Day 
1 
Day 
2 
Day 
3 
Day 
15 
(±3 
days) 
Day 
29 
(±3 
days) 
Day 
30 
(±3 
days) 
Day 
31 
(±3 
days) 
Day 8, 21, 
36, 43, 50, 
64, 71, 78 
(±3 days) 
Day 
57 
(±3 
days) 
Day 
85 
(±3 
days) 
Day 
113 
(±5 
days) 
Vital Signsj 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Digital Continuous and 
Triplicate 12-lead ECGk 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urine Drug Screenl; Cotinine; 
Alcohol Breath or Urine Test 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
Study Drug Administration 
SC Injection 
X 
 
Xm 
X 
Adverse Event Monitoring 
X 
X 
X 
X 
X 
Xm 
X 
X 
X 
X 
X 
X 
X 
X 
Abbreviations: AAT = alpha-1 antitrypsin; BMI = body mass index; ECG = electrocardiogram; ET = early termination; FSH = follicle stimulating hormone; PK = 
pharmacokinetic; SC = subcutaneous. 
a  Screening assessments can occur on multiple days, provided they are within the Day -28 up to Day -2 Screening period. 
b  If required per site SOP, admission on Day 14, and/or 28 is acceptable. 
c  Negative serum pregnancy test at Screening for WOCBP. Negative highly sensitive urine pregnancy test documented for WOCBP on Day -1 and prior to every dose. 
d  FSH only to confirm non-childbearing potential. 
e  COVID-19 testing if required per site SOPs. 
f  Safety laboratory tests include hematology, clinical chemistry, coagulation and urinalysis as noted in Table 11. Note that for urinalysis, abnormal results on dipstick or 
urinalysis should lead to laboratory urinalysis testing and/or urine microscopy. Any specific safety labs indicated in Table 6 will be collected according to the schedule in that 
table. When applicable and feasible, blood sampling should follow evaluations of vital signs and ECGs to reduce any impact on these measurements. 
g Predose plasma PK at every dosing visit. Specific time points for PK and select laboratory Weeks 0 and 4 provided in Table 6. Participants should stay in the clinic for 48 hours 
after the first and last doses to complete assessments. 

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h Full physical examination includes (at a minimum): alertness and orientation, general appearance, skin, head, eyes, ears, nose, throat, lungs, cardiovascular, gastrointestinal, 
musculoskeletal, and neurologic systems. Symptom-directed physical examinations to be performed as necessary. 
i  Height at Screening will be used for BMI calculations at all visits. 
j  Vital signs will be taken with the participant in the supine position after ≥5 minutes of rest. Temperature, respiratory rate, and SpO2 are measured once per time point. Blood 
pressure (systolic and diastolic) and pulse: measured ≤30 minutes pre-dose and 1 hr (±10 min), 2 hr (±10 min), 4 hr (±20 min), 12 hr (±1 hr) post dose on Day 1 and once at all 
other noted visits. Should additional post dose vital signs be collected per Site SOP, these should be captured in eCRF. 
k Continuous digital ECG monitoring for at least 48 hours from Day -1 through Day 2 and at least 24 hours through first day of last dose (Day 29); leads may be disconnected for 
~20 minutes following 24 hours after the first dose to allow for participant cleansing. Additional triplicate 12-lead ECGs are specified in Table 7. Note: only predose triplicate 
ECGs are required at Day 15. Participant must rest quietly for ≥5 minutes prior to triplicate ECGs. 
l  For drug screen panel, see Table 11 other screening tests. 
m Following the second dose (Week 2) all participants will be observed for safety evaluation in the clinic for at least 4 hours post study drug administration or per local SOP 
(whichever is longer). 
 
Table 6 
Plasma PK and Selected Laboratory Time Points (Period 2) 
 
Study 
Day/Specific 
Time 
Days 
1, 
15,29 
Days 1 and 29 
Days 2 and 30 
Days 3 and 31 
Weeks 1 through 
16 
Pre- 
dose 
Post dose 
≤30 
min 
prior 
to 
doseb 
30 min 
(±5 
min) 
1 hr 
(±5 
min) 
2 hr 
(±5 
min) 
4 hr 
(±10 
min) 
6 hr 
(±10 
min) 
8 hr 
(±10 
min) 
12 hr 
±10 
min) 
24 hr 
(±30 min) 
36 hr 
(±4 hr) 
48 hr (±4 hr) 
Visits 3 through 15 
Plasma PKa 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Every visit 
CBC, CRP, 
fibrinogen, 
coagulation, 
albumin 
X 
 
X 
 
X 
Day 2 only 
X 
Day 3 only 
Every visit 
Complement 
X 
X 
X 
X 
X 
Day 2 only 
X 
Day 3 only 
Weeks 1, 5, 6, and 8 
only 
Cytokinesc 
X 
X 
X 
X 
X 
Day 2 only 
X 
Day 3 only 
Weeks 1, 5, 6, and 8 
only 
Abbreviations: CBC = complete blood count; CRP = C-reactive protein; PK = pharmacokinetic. 
a Sufficient plasma PK sample to cover both WVE-006 and potential metabolites. When applicable and feasible, PK blood sampling should follow evaluations of vital 

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signs and ECGs to reduce any impact on these measurements. 
b Pre-dose laboratory results are NOT required prior to dosing 
c Cytokines samples will be collected and analyzed for: IL-1β, IL-6, IL-10, IL-12/23 (P40), IFN-γ, TNF-α, MCP-1, and MIP-1β 
 
Table 7 
Triplicate ECG Assessment Time Points (Period 2) 
 
Study Day/ 
Specific 
Time 
Day 1 
Days 1 and 29 
Days 2 and 
30 
Day 3 
Pre-first dose 
Post first and last doses 
-45 min 
±5 min 
-30 min 
±5 min 
-15 min 
±5 min 
30 min 
±5 min 
1 hr 
±5 min 
2 hr 
±5 min 
4hr 
±10 min 
6hr 
±10 min 
8hr 
±10 min 
12hr 
±10 min 
24hr 
±30 min 
48hr 
±4 hr 
ECGa 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Abbreviations: ECG = electrocardiogram 
a 
Digital ECG monitoring for at least 48 hours from Day -1 through Day 2 and at least 24 hours through first day of last dose (Day 29). Additional triplicate ECG measurements 
at the time points listed here. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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2 INTRODUCTION 
2.1 
Study Rationale 
WVE-006 is an oligonucleotide that was designed to specifically edit the Serpin Family A 
Member 1 (SERPINA1) mutant (Z) messenger ribonucleic acid (mRNA) back to wildtype (M). 
Editing of the SERPINA1-Z mRNA back to wildtype is expected to increase the concentration of 
M alpha-1 antitrypsin (M-AAT) protein in the serum and decrease the accumulation of Z-AAT in 
the liver, thus addressing both the lung and liver disease manifestations associated with 
Alpha-1 antitrypsin deficiency (AATD). 
WVE-006 is not expected to have pharmacological activity in healthy volunteers (HV) since they 
do not have the Serpin Family A Member 1 (SERPINA1) mutation. 
2.2 
Background 
AATD is a rare and clinically underrecognized condition that can affect the lung, liver, and 
rarely the skin. This disease can cause chronic obstructive pulmonary disease (COPD), a 
progressive, life-threatening lung disease, which results in severe shortness of breath, wheezing, 
chronic cough, and sputum production. In addition, these patients may present with asthma, 
chronic lung disease, emphysema, recurring chest infections, bronchitis, and bronchiectasis. 
AATD can also cause life-threatening liver disease, skin problems (panniculitis), and 
inflammation of the blood vessels (vasculitis). There are currently very limited treatment options 
for AATD, most of which are based on symptom management. 
AATD is caused by pathogenic variants in the SERPINA1 gene and is inherited in an autosomal 
and codominant manner, indicating that the two alleles are active and contribute to the genetic 
trait (Greene et al., 2016). The M allele is the most common allele of the alpha-1 gene and 
produces normal levels of M-AAT. The Z allele is the most common variant of the gene and 
results in 95% of severe cases of AATD (Strnad et al., 2020). The Z mutation of the SERPINA1 
gene results from a G-to-A missense mutation corresponding to a glutamic acid to lysine amino 
acid change at position 342 in the protein. The Z-AAT protein is misfolded and prone to 
aggregation in hepatocytes in a gain of function toxicity in the liver (which may lead to fibrosis, 
cirrhosis, or increased risk of hepatocellular carcinoma) and decreases the secretion of functional 
AAT into serum, resulting in a loss of functional AAT in the lung (Strnad et al., 2020). 
WVE-006 is an investigational A-to-I editing oligonucleotide (AIMer) that was designed to 
specifically edit the SERPINA1-Z RNA back to wildtype. 
2.3 
Benefit/Risk Assessment 
The information generated by this study will provide a better understanding of the study drug’s 
safety profile and how it is distributed through and works in the human body. No significant 
toxicity is expected in treated participants since WVE-006 is targeted to mutant SERPINA1-Z 
RNA which will not be present in the study population. Only participants with wild type PI*MM 

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2.3.2 
Benefit Assessment 
Since all participants will be HV without the SERPINA1-Z mutation, no direct benefits are 
expected for study participants. The knowledge gained from this testing may help to further 
develop WVE-006 as an effective treatment for patients with AATD. 
2.3.3 
Overall Benefit-Risk Conclusions 
Risks to participants in this study have been minimized by the comprehensive safety assessments 
and the systematic review of safety data by the Data Monitoring Committee (DMC), and as such 
the risks are justified by the anticipated benefits that may be eventually afforded to patients with 
AATD. 
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3 OBJECTIVES, ENDPOINTS, AND ESTIMANDS 
Table 8 
Study Objectives and Endpoints for WVE-006-001 
 
Primary Objective: 
Primary Endpoint: 
• 
To evaluate the safety and tolerability of 
WVE-006 
• 
Incidence of treatment emergent adverse events 
(TEAEs), related TEAE, severe TEAE, serious 
TEAE 
• 
Changes in safety assessment parameters 
(i.e., physical exam, vital signs, clinical 
laboratory results, ECGs (including any changes 
to QTcF) 
• 
Tolerability based on incidence of 
discontinuation due to TEAEs 
Secondary Objective: 
Secondary Endpoints: 
• 
To evaluate the PK of WVE-006 after a single 
dose in healthy participants 
• 
To evaluate the PK of WVE-006 after multiple 
doses in healthy participants 
• 
PK parameters of WVE-006 in plasma, 
including AUCinf, AUC0-24h, AUC0-48h, AUClast, 
Cmax, tmax 
• 
PK parameters of WVE-006 in plasma 
following the first and last doses, including 
AUCtau, AUC0-24h, AUC0-48h, AUClast, Cmax, tmax 
Exploratory Objectives: 
Exploratory Endpoints: 
• 
To evaluate urine excretion of WVE-006 
• 
Ae, Ae%, and cumulative Ae% (cum Ae%) for 
parent drug, as well as potential metabolites in 
urine 
Abbreviations: Ae=amount excreted; AUC=area under the curve; C=concentration; ECG=electrocardiogram; PK=pharmacokinetic; t=time; 
TEAE=treatment-emergent adverse event 

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4 STUDY DESIGN 
4.1 
Overall Study Design 
This is a double-blind, placebo-controlled, single ascending dose (SAD) and multidose Phase 1 
study to assess the safety, tolerability, and PK of WVE-006 in healthy participants. Participants 
will be randomized to WVE-006 or placebo. 
Period 1 will evaluate single ascending doses of WVE-006 in up to five cohorts of up to 8 
healthy participants each (3:1 active:placebo). An additional cohort (Cohort 6) may be included 
to evaluate concentration-QTc. Participants may be on-study for up to 12 weeks. A sentinel 
strategy will be employed for the first 2 participants (1 active:1 placebo) of every new dose level 
during the SAD portion (Period 1) and in the multiple dose portion (Period 2) of the study, with a 
48-hour observation period to assess for acute safety events. The Dose Escalation Committee 
(DEC) and the DMC will review available data through Day 8 that will include key PK 
parameters and safety for each dose cohort, as well as previously accumulated safety data and 
available PK data, to recommend subsequent dose escalation. Additional details are provided in 
Section 4.1.2. 
Dose Escalation Stopping Criteria (Period 1): 
Dose escalation will be paused until further evaluation by the DMC if any of the following 
criteria are met. If it is confirmed that a stopping criterion was met, no further dosing will take 
place until after submission and approval of a substantial amendment if the DMC recommends 
the trial can continue. 
• One or more at least possibly related Common Terminology Criteria for Adverse Events 
(CTCAE) Grade ≥3 TEAE or CTCAE grade ≥3 laboratory abnormality in a single cohort. 
o All grade 3 toxicities for vital signs must be confirmed with a repeat measurement 
obtained within 1 hour. 
o All grade 3 toxicities for laboratory parameters must be confirmed with a repeat 
measurement obtained within 24 hours. 
• Two or more at least possibly related CTCAE grade ≥2 TEAEs or CTCAE Grade ≥2 
laboratory abnormalities in a single cohort. 
o All grade 2 toxicities for vital signs must be confirmed with a repeat measurement 
obtained within 1 hour. 
o All grade 2 toxicities for laboratory parameters must be confirmed with a repeat 
measurement obtained within 24 hours. 
• Any at least possibly related SAE in a single cohort. 
In Period 2, a single cohort of up to 8 healthy participants including up to 6 WVE-006 and 
2 placebo treated participants (3:1 active:placebo) will receive multiple doses of WVE-006. 
Participants may be on-study for up to 16 weeks. The DEC and DMC will review available 

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safety and PK data from Period 1 to select the maximum tolerated dose level (MTD) or other 
selected dose achieved if MTD was not reached. Additional information about treatment is 
provided in Section 4.1.2. Individual treatment stopping criteria for participants in Period 2 are in 
Section 7.1.1. 
4.1.1 
Screening 
Screening will determine participant eligibility for the study and begins when the participant 
signs the study informed consent form (ICF). Potential participants will initiate screening up to 
4 weeks prior to dosing. The required screening evaluations for participants in the study are 
outlined in the Schedule of Assessments (SOA; Section 1.3). 
Screening assessments can occur on multiple days, provided they are within the Screening period 
(Day -28 up to Day -2). The Investigator will determine whether participants meet eligibility 
criteria (see Section 5.1 and Section 5.2). 
For management of screen failures, refer to Section 5.3. 
4.1.2 
Treatment 
Period 1: Single Ascending Dose 
Period 1 will evaluate single ascending doses of WVE-006 in up to five cohorts of up to 8 
healthy participants each. Each cohort will include up to 6 WVE-006-treated and 2 
placebo-treated participants (3:1 active:placebo). Participants will receive a single SC dose of 
WVE-006 or placebo on Day 1. 
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A sentinel strategy will be employed for the first 2 participants (1 active, 1 placebo) of every new 
dose level during the SAD portion of the study. The sentinel participants will be dosed and 
monitored in the clinic for 48 hours to identify any potential acute safety events. If neither of 
these sentinel participants experiences stopping criteria and if there are no other safety concerns 
during this 48-hour period, the remaining 6 participants will be randomized in a blinded fashion 
to active study drug (n=5) or placebo (n=1) and may be dosed on the same day. These 
participants will be observed in clinic for 48 hours after administration of study drug. 
Participants will attend weekly clinic visits on Weeks 0 through 12 to be followed for safety, 
tolerability, and PK assessments through Day 85 per the SoA. 
If Period 1 Dose Escalation Stopping Criteria (see Section 4.1) are met at any point, dosing will 
be paused until further review and confirmation by the DMC. No further dosing will take place 
until after submission and approval of a substantial amendment if the DMC recommends the trial 
can continue. 
Period 2: Multiple Doses 
In Period 2, a single cohort of up to 8 healthy participants, including up to 6 WVE-006 and up to 
2 placebo treated participants (3:1 active:placebo), will participate in a multidose assessment of 
WVE-006. A sentinel strategy will be employed for the first 2 participants (1 active:1 placebo), 
with a 48-hour observation period to assess for acute safety events. The DEC and DMC will 
review available safety and PK data from Period 1 to select the MTD with an acceptable PK 
profile. The MTD is defined as the dose below a dose level where any of the dose escalation 
stopping rules were met. If MTD is not achieved in Period 1 (i.e., no dose escalation stopping 
rules were met and all doses were well tolerated), then the highest dose reached in Period 1 will 
likely be selected for Period 2, though the DEC and DMC may select a lower dose based on all 
available information. At least 4 weeks of safety data for the proposed dose and all available data 
from the study must be available from Period 1 in order to inform the DEC and DMC Period 2 
dose selection. WVE-006 or placebo will be administered every other week (Q2W) over 4 weeks 
(total of 3 doses; Weeks 0, 2, and 4). Following the first dose (Week 0) and last dose (Week 4), 
participants will stay in the clinic for at least two nights for PK assessments. Following the 
second dose (Week 2) all participants will be observed for safety evaluation in the clinic for at 
least 4 hours post-study drug administration or per local SOP (whichever is longer). 
In Period 2, dosing will be paused or discontinued (per Investigator judgment) for an individual 
participant; see Section 7.1.1 for additional details. 
4.1.3 
Follow-up 
Following completion of study treatment, participants will continue to have follow-up visits for 
up to 12 weeks. Safety assessments will be completed and safety laboratory samples, and PK 
samples will be drawn during these visits. Refer to Table 1 for Period 1 and Table 5 for Period 2 
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Dose Escalation 
The planned initial dose for Period 1 is 30 mg (Period 1, Cohort 1). Subsequent dose levels will 
be determined by the DEC and DMC based on previous Period 1 cohort data and will not exceed 
a 
 increase of the prior dose. The maximum dose will not exceed the limit specified in 
Section 4.1.2. Dosing decisions will be communicated directly to the site. 
If adequate safety and tolerability is observed in the initial dose cohorts (Cohorts 1 to 5) and no 
cohort stopping criterion was met, an optional cohort (Cohort 6) may be conducted in order to 
characterize the safety, tolerability, PK and the relationship between drug concentration and QTc 
prolongation at an appropriate dose. 
The MTD level from Period 1 will be selected to be explored in Period 2. If the MTD is not 
achieved in Period 1 and the top dose is well tolerated, then the top dose will likely be selected 
for Period 2. The projected PK/PD profiles support every other week dosing regimen, but this 
recommendation is subject to change once clinical data become available. The DEC and DMC 
may select a lower dose based on all available information. 
The exposures of the selected doses during Period 1 and Period 2 of the study will not exceed the 
observed exposures at the NOAEL. 
4.4 
End of Study Definition 
The end of the study is defined as the date of the last visit of the last participant in the study. 
A participant is considered to have completed the study if the participant has completed all study 
visits including Week 12 for Period 1, Week 16 for Period 2, or the ET visit. 
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5 STUDY POPULATION 
Participants must meet all inclusion criteria and none of the exclusion criteria during screening. 
For eligibility purposes, abnormal laboratory or vital signs or ECG results may be repeated once 
during the Screening period or Day -1 (as applicable) for confirmation if an abnormal result is 
observed at the initial assessment. 
Participants who do not meet all inclusion/exclusion criteria will be considered screen failures. 
Participants who fail screening may be rescreened; for handling of screen failures and 
rescreening, refer to Section 5.3. 
Deviations to recruitment and enrollment criteria, also known as eligibility waivers or 
exemptions, are not permitted. 
5.1 
Inclusion Criteria 
Participants are eligible to be included in the study only if all of the following criteria apply: 
1. Participant is capable of understanding and be willing to provide written informed consent 
prior to any study-related procedures. 
2. Participant is capable of understanding and adhering to all the requirements, procedures, 
instructions, and restrictions required by the protocol including scheduled visits, drug 
administration plan, laboratory tests, and likely to complete the study as planned. 
3. Healthy as determined by the Investigator, based on a medical evaluation, including medical 
history, concomitant medications, full physical examination, vital signs, laboratory tests, and 
ECGs at Screening and Day -1. Per Investigator’s judgement, there should be no evidence of 
cardiovascular, pulmonary, endocrine, hepatic, biliary, gastrointestinal, neurological, 
hematological, immunological, metabolic, skeletal, renal, psychiatric disorders, or cancer 
within the past 5 years prior to Screening Visit (except localized or in situ cancer of the skin). 
Clinical abnormality or laboratory parameter(s) outside normal range must not be clinically 
significant or unlikely to introduce additional risk to the participant nor interfere with the 
study procedures nor the interpretation of any of the study assessments. 
4. Male or female healthy participants 18-65 years of age at Screening Visit. 
5. Participant has a body mass index (BMI) between 18 to 32 kg/m2 inclusive at Screening and 
Day -1 Visits. 
6. Genetic testing confirming PI*MM. 
7. Participant has been a non-smoker for at least 1 year prior to screening and agrees to abstain 
from tobacco and nicotine containing products for the duration of the study. 
8. Women of childbearing potential (WOCBP) must be: 
a. Non-pregnant as determined by a negative serum pregnancy test at Screening and 
negative highly sensitive urine pregnancy test on Day -1. 
b. Non lactating. 

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c. Agree to use a highly-effective method of contraception (as defined in Section 10.4) from 
 prior to Day 1 and for at least 
 following last study drug administration. 
Exception: Women exclusively engaging in same-sex sexual activities are not required to 
meet this criterion. 
d. Must be willing to forgo ova (egg) donation for at least 
 following the last study 
drug administration. 
9. Women of non-childbearing potential are defined as meeting at least 1 of the following 
criteria: 
a. At least 12 months post-menopausal and has an FSH >40 mIU/mL. 
b. Surgically sterile, defined as having a documented bilateral oophorectomy, or 
hysterectomy. 
10. Male participants must be willing to follow contraceptive requirements (as defined in 
Section 10.4) and should not impregnate anyone while they are in the study and for at least 
 following the last dose of study drug. In addition, participant must be willing to 
forgo sperm donation for at least 
 following the last dose of study drug. Men 
exclusively engaging in same-sex sexual activities are not required to meet this criterion. 
5.2 
Exclusion Criteria 
Participants are excluded from the study if any of the following criteria apply: 
1. Participant has a history of multiple drug allergies or of allergic reaction to an 
oligonucleotide or to N-acetylgalactosamine (GalNAc). 
2. Participant has a history of intolerance or any medical condition that might interfere with SC 
injection(s). 
3. History or signs or symptoms of severe (bacterial, viral, parasitic, or fungal) infection within 
4 weeks prior to Screening or Day 1 Visits. 
4. History or signs or symptoms of an acute illness (including COVID-19) within 10 days prior 
to dosing on Day 1 Visit. Exception: mild seasonal allergies. 
5. Positive COVID-19 test at time of Screening (if required per site SOP) and at Day -1 Visit. 
6. Participant received a COVID-19 or any other vaccine within 14 days before dosing on 
Day -1 Visit or is scheduled for vaccination anytime during the study. 
7. Participant has total bilirubin > upper limit of normal (ULN) though participants with 
documented Gilbert’s syndrome with normal conjugated bilirubin are eligible; aspartate 
transaminase (AST) and/or alanine transaminase (ALT) >ULN at Screening and Day -1. 
8. Participant has estimated glomerular filtration rate (eGFR) ≤60 ml/min/1.73mm2 (calculated 
by the Cockcroft-Gault formula) at Screening and Day -1. 
9. Participant has a positive serology for hepatitis B or hepatitis C at Screening; participants 
with positive hepatitis B serology may be enrolled if there is evidence the participant 
received HBV immunization. 
10. Participant is known to be positive for human immunodeficiency virus (HIV) and/or positive 
serology for HIV 1/2 where testing is permitted per local regulations. 
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11. Participant has a history of regular alcohol consumption exceeding 14 standard drinks/week. 
1 standard drink is equivalent to 14g ethanol or 5 US fluid ounces (fl oz) (150 mL) of wine 
(approximately 12% alcohol by volume), 12 fl oz (360 mL) of beer (approximately 5% 
alcohol by volume), or 1.5 fl oz (45mL) of hard liquor (approximately 40% alcohol by 
volume), within 1 year prior to the Screening Visit. 
12. Participant has a history of caffeine consumption exceeding 8 cups of coffee/day 
(1 cup = 8 fl oz [240mL]) within 14 days prior to first study dose, or consumption of any 
caffeine or chocolate containing products for 3 days prior to clinical research unit (CRU) 
admission. Caffeine-containing food and/or beverages (e.g., tea, cola) should be considered 
equivalent to coffee. 
13. Unwilling to abstain from alcohol for 48 hours prior to dosing at each of the dosing visits. 
14. Participant has a positive alcohol test at Screening and/or Day -1 Visits. 
15. Any prescribed or recreational substance use (irrespective of legality) within 6 months prior 
to screening or unwilling to refrain from such use for the duration of the study. 
16. Positive drug screen at Screening and/or Day -1 Visits. 
17. Positive cotinine test at Screening and/or Day -1 Visits. 
18. Use of prescription or non-prescription medications, including vitamin, dietary, and herbal 
supplements (including St John’s Wort) within 7 days or 5 half-lives (whichever is longer) 
prior to the first dose of study treatment unless, in the opinion of the Investigator and 
Sponsor, the medication will not interfere with interpretation of study assessments. 
Contraception and hormone replacement therapy (HRT) are permitted. If needed, over-the- 
counter (OTC) medications such as paracetamol/acetaminophen may be used acutely. 
19. History of major surgery in the 3 months prior to Screening Visit and/or planned surgery for 
the duration of the study. 
20. Sustained hypertension defined as at least 2 repeated measurements at least 15 minutes apart 
of systolic pressure exceeding 130 mm Hg and/or diastolic pressure exceeding 80 mm Hg at 
Screening and/or Day -1 Visits. 
21. Supine pulse rate <45 beats per minute (bpm) or >100 bpm at Screening and/or 
Day -1 Visits. 
22. One or more of the following abnormal ECG findings at Screening and/or Day -1 Visits: 
a. Second- or third-degree atrioventricular block 
b. QRS >120 msec 
c. QTcF >450 msec for males or >470 msec for females 
d. PR interval >200 msec 
e. Any rhythm other than sinus rhythm that is considered clinically significant by the 
Investigator. 
23. History of risk factors for Torsade de Pointes including unexplained syncope, known long 
QT syndrome, heart failure, myocardial infarction, angina, or clinically significant abnormal 
laboratory assessments including hypokalemia, hypercalcemia, or hypomagnesemia. 
24. Family history of long QT syndrome or Brugada syndrome. 

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25. Donation of blood or blood products in excess of 500 mL within 12 weeks prior to Screening 
Visit and/or unwilling to refrain from blood donation for the duration of the study. 
26. Participant has any medical or social condition which in the opinion of the Investigator, 
would make the participant unsuitable for participation in the study, for study treatment, or 
could interfere with the assessments of safety or PK, or completion of the study. 
27. Participant has received an investigational agent within 3 months or 5 half-lives (if known), 
or twice the duration of biological effect (if known), whichever is longer, before Screening, 
or who is in follow-up of another clinical study of an investigational agent at the time of the 
Screening Visit. 
28. Exposure to more than 4 new chemical entities within 12 months prior to the Day 1 Visit. 
29. Prior treatment with any oligonucleotide or small interfering RNA within 12 months prior to 
the Day 1 Visit. 
30. Participant is directly or indirectly involved in the conduct and administration of this trial as 
an Investigator, sub-investigator, trial coordinator, or other trial staff member, or the 
participant is a first-degree family member, significant other, or relative residing with one of 
the above persons involved directly or indirectly in the trial. 
5.3 
Screen Failures 
A screen failure occurs when a participant who has consented to participate in the clinical study 
is not subsequently randomized to study drug. A minimal set of screen failure information will 
be collected in the electronic data capture (EDC) system and will include date of informed 
consent, demography (as allowed by local law), failed eligibility criteria, and SAEs. 
Individuals who fail screening may be rescreened after discussion with Sponsor's Medical 
Monitor. Participants should be assigned a new participant number for every 
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6 STUDY DRUGS AND CONCOMITANT THERAPY 
Study drugs are all pre-specified, investigational products intended to be administered to the 
study participants during the study conduct. 
6.1 
Study Drugs Administered 
Study drugs include WVE-006 and placebo. Details on study drugs are provided in Table 9. 
Table 9 
Study Drugs Administered 
 
Study Drug Label 
WVE-006 
Placebo 
Study Drug Name 
WVE-006 
Placebo 
Study Drug Description 
Period 1: SC injection, one dose per 
participant at varying dose levels. 
Period 2: SC injection, Q2W at a dose 
level identified in Period 1. 
Period 1: SC injection, once per 
participant. 
Period 2: SC injection, Q2W. 
Type 
Drug 
Drug 
Dose Formulation 
Lyophilized powder for reconstitution 
0.9% normal saline, sterile solution for 
injection 
Unit Dose Strengths 
 per vial 
N/A 
Dosage Levels 
Period 1: single dose 
Starting Dose: 30 mg 
Highest dose: see Section 4.1.2 
Period 2: Q2W dosing for a total of 3 
doses at the dose level selected from 
Period 1 
N/A (same volume as corresponding 
WVE-006 dose) 
Route of Administration 
SC injection 
SC injection 
Use 
Experimental 
Placebo 
Sourcing 
Provided centrally by the Sponsor 
Provided locally by the site 
Packaging and Labeling 
Study drug will be provided in 10 mL 
single use vial. Each vial will be 
labeled as required per country 
requirement. 
N/A 
Abbreviations: SC = subcutaneous; Q2W = every other week 
 
Table 10 
Study Periods 
 
Period Title 
Period 1 
Period 2 
Period Type 
Single ascending dose 
Multiple dose 
Period Description 
Participants will receive WVE-006 or 
placebo once SC starting at 30 mg and 
escalating as per the study schema. 
Participants will receive a total of 3 doses 
of WVE-006 or placebo Q2W SC at the 
MTD, highest dose, or other selected dose 
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Participants will be followed for 
12 weeks. 
from Period 1. Participants will be 
followed for 12 weeks following last 
study drug administration. 
Associated Study Drug 
Labels 
WVE-006, Placebo 
WVE-006, Placebo 
6.2 
Preparation, Handling, Storage, and Accountability 
1. The Investigator or designee (e.g., pharmacy staff) must confirm appropriate conditions 
(e.g., temperature) have been maintained during transit for all study drug received, and 
any discrepancies are to be reported and resolved before use of the study drug. 
2. Only participants enrolled in the study may receive study drug, and only authorized site 
staff may supply, prepare, or administer study drug. 
3. WVE-006 must be stored in a secure, environmentally controlled, and monitored (manual 
or automated) area in accordance with the labeled storage conditions with access limited 
to the authorized pharmacy staff. 
4. The designated staff is responsible for study drug accountability, reconciliation, and 
record maintenance (i.e., receipt, reconciliation, and final disposition records). 
5. The Investigator, pharmacy, and site staff must ensure that study blind is maintained; see 
Section 6.5 for more information. 
6. Returned study drug should not be re-dispensed to participants. 
7. Further guidance and instructions for the preparation, handling, storage, accountability, 
and disposition of study drug is provided in the Pharmacy Manual. 
6.3 
Study Drug Administration 
Study drug will be dispensed at the study visits as summarized in the SoA. 
Participants are dosed at the site and will receive study drug directly from the Investigator or 
designee, under medical supervision. Anatomical SC injection sites will be determined by the 
Investigator for each participant; if the abdomen is selected as an injection site, it is 
recommended that the participant be supine when the injection is administered. Rotation of 
injection sites for multiple dose period is allowed per the Investigator’s judgment. The date, 
time, and anatomic location of each dose administered in the clinic will be recorded in the source 
documents and eCRF. The dose of study drug and study participant identification will be 
confirmed at the time of dosing by a member of the study site staff other than the person 
administering the study drug. Please refer to the Study Manual for additional details regarding 
administration of study drug. 

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6.4 
Assignment to Study Drug 
All participants will be assigned to randomized study drug per assigned randomization schedule. 
Details will be provided in the randomization plan and executed per site standard. 
6.5 
Blinding 
In order to maintain the blinding of the study drug (WVE-006 or placebo), all study personnel 
will be blinded to participant treatment assignment. Physicians, nurses, participants, contract 
research organization (CRO) staff, and any study personnel performing participant assessments 
must NOT be informed of the participant’s treatment assignment (see Study Manual) except if 
unblinding is required or as required by regulatory authorities (Section 6.5.1). 
The pharmacy personnel will be unblinded to prepare doses of study drug to ensure that the 
clinical site staff responsible for administering study drug and conducting assessments per the 
protocol, and the participant remain blinded to study treatment. In addition, a clinical research 
associate will be unblinded to perform drug accountability. 
6.5.1 
Breaking the Blind 
6.5.1.1 
Unblinding In Case Knowledge of Treatment May Impact Medical 
Management 
To maintain the overall quality of data collected during the study, breaks in blinding during the 
conduct of the study should occur only in exceptional circumstances when knowledge of the 
actual treatment is essential for further management of the participant. Unblinding of the study 
drug for an individual can be done during the study period in the case of: 
• 
Any AE where knowledge of the treatment assignment is deemed necessary to treat the 
participant 
• 
Pregnancy of a participant or participant’s partner in the study 
Procedures for unblinding will be described in a Study Manual supplied to the site. The 
investigator should make every effort to contact the Sponsor’s Medical Monitor before 
unblinding a participant’s treatment assignment unless this could delay emergency treatment of 
the participant. In all circumstances other than a medical emergency, unblinding will be done 
only after discussion with the Sponsor’s Medical Monitor. Emergency treatment unblinding must 
be reported to the Sponsor’s Medical Monitor immediately. When it is necessary to break the 
blind, the investigator must notify the Ethics Committee (EC)/Institutional Review Board (IRB) 
as applicable. If a participant is unblinded, the participant will discontinue further treatment with 
study drug (i.e., MD) and will have either a routine scheduled visit if due or an unscheduled visit 
as soon as possible to evaluate the safety concern that prompted the unblinding. 
If unblinding is deemed necessary, the Investigator should not disclose the treatment assignment 
to other study personnel until after database lock. 

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6.5.1.2 
Recording the Unblinding 
If an unblinding occurs, the following information should be captured at a minimum: 
• Participant information 
• Reason for unblinding 
• Date and time of unblinding 
• Name of the person requesting/responsible for unblinding. 
How unblinding should be reported to the Sponsor will be detailed in a Study Manual. 
6.6 
Study Drug Compliance 
The date, time, and anatomic location of each dose administered in the clinic will be recorded in 
the source documents. Errors in administration (e.g., incorrect dose, injection to incorrect 
anatomic area) or unexpected issues with injection should be documented and reported to the 
Sponsor’s Medical Monitor. 
6.7 
Dose Modification 
Dose modifications are not applicable in Period 1 since only a single dose will be administered 
per participant. 
Participants in Period 2 will receive the DMC-approved dose at the time of their enrollment. If 
the DMC determines that a dose reduction is needed AFTER treatment in Period 2 has started, 
participants who have started study treatment in Period 2 will receive their remaining doses at 
the reduced dose level. 
For dose modifications due to TEAEs, refer to Section 7.1.2. 
6.8 
Continued Access to Study Drug after the End of the Study 
Continued access to WVE-006 is not planned following the end of study. 
6.9 
Treatment of Overdose 
The study drugs are planned to be administered by trained study staff. Administration will be 
performed in accordance with this protocol and instructions in a Study Manual. Any incidence of 
overdose should be recorded as a deviation. 
No data are available regarding overdose with WVE-006. As with any agent, if overdose occurs, 
general supportive measures and close observation should be instituted. Misuse of the study drug 
is not expected in this study as participants have no direct access to the study drug. 

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6.10 Prior and Concomitant Therapy 
Medications with a start date before the first dose of investigational drug will be classified as 
prior medications. Any medication that the participant began taking after the first dose of 
investigational drug will be classified as concomitant. Any medication that a participant started 
before the first dose of investigational drug and continued to take during the study will be 
classified as both prior and concomitant. Any medication that was stopped on the same day as 
the first dose of investigational drug will be considered a prior medication. If the stop date of a 
given medication is missing, then the medication will be classified as concomitant. 
It is required that the drug name, dose, indication, and the dates of administration are to be 
recorded. This will include all prescription drugs, herbal products, vitamins, minerals, and 
over-the-counter medications. Any changes in concomitant medications will also be recorded in 
the participant’s electronic case report form (eCRF). 
Any concomitant medication deemed necessary for the welfare of the participant during the 
study may be given at the discretion of the Investigator. However, prophylactic medications for 
injection site reactions are NOT permitted unless first discussed between the Investigator and 
Medical Monitor. 
Prescription or non-prescription drugs, including vitamins, herbal and dietary supplements 
should not be taken throughout the duration of the study unless required to treat an AE, with the 
exception of paracetamol and ibuprofen. 
 
Participants should not receive a vaccination, including COVID-19 vaccine injection, within 
14 days prior to first dose until completion of the post-study follow up visit. 
If intake of any prior or concomitant medication is necessary during the study, the daily dosage, 
duration and reasons for administration will be recorded on the participant’s eCRF. 

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7 DISCONTINUATION OF STUDY DRUG AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL 
Participants are free to withdraw from the study or discontinue study treatment at any time upon 
request without prejudice to their future medical care by the Investigator or at the study site. 
Participation in the study may also be stopped at any time at the discretion of the Investigator or 
at the request of the Sponsor. Participants who withdraw or discontinue from study treatment 
will no longer receive investigational drug. 
7.1 
Discontinuation of Study Treatment in Period 2 
A participant must permanently discontinue study treatment for any of the following: 
• The participant is withdrawn from the study (Section 7.1.2). 
• The participant experiences an AE that in the Investigator’s opinion requires treatment 
discontinuation. 
• A change in the participant’s medical condition not consistent with the protocol 
requirements or that justifies discontinuation of study drug. 
• Pregnancy (refer to Section 10.3.6). 
If a participant discontinues treatment, they will be encouraged to complete the ET visit, unless 
consent is withdrawn. 
The reason for discontinuation of study treatment must be recorded in the eCRF and source 
documentation. 
7.1.1 
Period 2 Individual Stopping Criteria: 
Dosing will be paused or discontinued (per Investigator judgment) for an individual participant 
at any time in the study if: 
• Participant experiences any severe event or SAE considered at least possibly related to 
study drug. 
• Participant experiences clinically significant hypersensitivity to WVE-006 (or placebo) 
administration. 
• Participant has any medical condition that is judged by the Investigator to jeopardize the 
participant’s safety if he or she continues to receive the study drug. 
7.1.2 
Withdrawal of Participants from the Study 
Participants must be withdrawn from the study for any of the following: 
• The participant withdraws consent 
• At the discretion of the Investigator for medical reasons 

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• At the discretion of the Investigator or Sponsor for noncompliance 
• Major protocol deviation that may impact interpretation of data (after discussion with 
Sponsor) (see Section 10.5.2) 
• Termination of the study by the Sponsor (see Section 10.1.9) 
• At the discretion of the Sponsor for any reason 
Any participant for whom consent to participate in the study is withdrawn will be removed from 
further treatment and study observation immediately upon the date of request. If possible, the 
early termination study procedures (Section 4.1.4) and observations should be completed before 
the participant withdraws consent. All information, including the reason for withdrawal from the 
study (if known), must be recorded in the eCRF and source documentation. Any information 
collected prior to withdrawal of consent will be used for study purposes. 
7.2 
Dose Interruption 
In Period 2, if a participant is unable to be dosed at a visit, all other assessments planned for that 
visit per the SoA (Section 1.2) should still be conducted as planned with the exception of PK 
samples which do not need to be collected. If participant is unable to come to clinic for a visit, 
that entire visit will be skipped. 
If a TEAE caused the second dose to be skipped for a participant in Period 2, it should have 
resolved or returned to baseline before the participant is restarted on study treatment after 
consultation with the Sponsor’s Medical Monitor. 
7.3 
Lost to Follow-up 
Participants who fail to return for assessments will be contacted by the site in an attempt to have 
them comply with the protocol. A minimum of 3 documented contact efforts should be made on 
different days over the course of 2 weeks. If site requirements to consider a participant lost to 
follow-up are more stringent, the site requirements must be fulfilled. Contact efforts can include 
phone call, text message, email, or contacting the participant’s partner (if applicable). If the 
participant is unreachable, a registered letter will be sent to the participant requesting him or her 
to contact the study center. If contact with the participant is not established after all above 
attempts, this participant will be considered as lost to follow-up. 
7.4 
Replacements 
In Period 1 or 2, additional participants may be enrolled as replacements for discontinued or 
withdrawn participants (refer to Section 7) in consultation with the Sponsor. 
Any participants enrolled but withdrawn prior to the first dose will be replaced. Any participants 
withdrawn or discontinued after receiving at least one dose may be replaced at the discretion of 
the Sponsor. 

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Enrollment/randomization numbers will not be reused. A new, unique enrollment/randomization 
number will be given to the new participant. 

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8 STUDY ASSESSMENTS AND PROCEDURES 
Study procedures and their timing are summarized in Section 1.2. Additional details of each 
assessment are given below. Screening assessments must meet eligibility criteria as listed in 
Section 5. Deviations from protocol procedures are not allowed unless required to protect the 
immediate safety of the participant. In such instances, the Investigator should make every 
attempt to discuss the need with the Sponsor’s Medical Monitor in advance, but no later than 
within 24 hours after the deviation was implemented. The safety reason(s) for the deviation 
should be documented. 
Results of assessments will be recorded in the eCRF and source documents. In general, any 
assessment or result the Investigator considers clinically significant should be recorded as an AE. 
8.1 
General Baseline and Administrative Assessments 
8.1.1 
Medical History and Demographics 
A general medical history will be obtained at the Screening Visit. Investigator assessment of past 
medical history at Screening will include information regarding any significant medical, surgical, 
and psychiatric conditions and treatments. 
Demographic data will be collected. 
8.1.2 
Height and Weight 
The participant’s height and weight will be measured at the time points described in the SoA. To 
the extent possible, the same scale should be used through the study. BMI will be automatically 
calculated based on the entered height and weight and will not need to be manually entered. 
8.1.3 
Eligibility Criteria Review 
The Investigator will review the participant’s social history, Screening laboratory, and other 
assessments to confirm that the participant meets all eligibility criteria. 
8.1.4 
Drug, Alcohol, and Cotinine Screening 
A commercially available urine drug screen, alcohol breath or urine test, and cotinine screen will 
be conducted at the time points described in the SoA. Screening results must meet eligibility 
criteria. Positive results while the participant is on study must be recorded in the participant’s 
medical record and discussed with the Medical Monitor. 
Participants will be instructed to not eat food containing poppy and/or sesame seeds for 3 days 
before each visit to the Clinical Unit, as consumption of poppy and/or sesame seeds can lead to a 
positive opiate result in the drugs of abuse test. 

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8.1.5 
Follicle Stimulating Hormone 
FSH testing will be done at Screening only as needed to confirm a female participant is not of 
child-bearing potential. 
8.1.6 
Viral Serology 
Viral serology for hepatitis B, hepatitis C and HIV 1/2 (where testing for HIV is permitted per 
local regulations) will be conducted at Screening to confirm the participant meets eligibility 
criteria. 
8.1.7 
COVID-19 Testing 
If applicable, COVID-19 testing will be performed per site SOP at Screening and/or on Day -1 to 
ensure the participant meets eligibility criteria. Additional COVID-19 testing may be performed 
if required during the conduct of the study, per site SOPs, at other visits. 
8.2 
Efficacy Assessments 
There are no efficacy assessments as this HV study is focused on safety and PK. 
8.3 
Safety Assessments 
The safety assessments will include the following: 
• AEs 
• Concomitant medications 
• Full and symptom-directed physical examinations 
• Vital signs 
• Weight / BMI 
• Digital continuous and triplicate 12-lead ECGs 
• Clinical laboratory evaluations (as per Table 11) 
• Pregnancy testing (if applicable) 
Strenuous exercise must be completely avoided from 3 days before the first dose of study drug 
until the final study visit. 
See Section 10.3 to determine if abnormal laboratory test results or other safety assessments 
qualify as AEs. 

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8.3.1 
Prior and Concomitant Medications 
It is the responsibility of the Investigator to ensure that details regarding the medication(s) are 
recorded in full in the eCRF. Refer to Section 6.10 for more details regarding prior and 
concomitant medications. 
8.3.2 
Physical Examination 
At Screening, a full physical examination will include (but is not limited to) an examination of 
skin, head, eyes, ears, nose, throat, respiratory, cardiovascular, gastrointestinal, endocrine, 
metabolic, blood, lymphatic, musculoskeletal, psychiatric, and neurologic (including mental 
status, cranial nerves, motor system, reflexes, coordination and gait, and sensory system) 
systems. A full physical examination is required at other visits, as noted in the SoA. 
At some time points, a symptom-directed physical examination will include systems to be 
evaluated as appropriate for the participant’s condition and symptoms. 
8.3.3 
Vital Signs 
Vital sign measurements will be taken with the participant in a supine position after the 
participant has been resting quietly for a period of at least 5 minutes. Blood pressure (systolic 
and diastolic), temperature, pulse, respiratory rate, and SpO2 will be measured by qualified 
personnel at the time points described in the SoA. If the initial reading is high, the measurements 
will be repeated once to confirm the results. 
8.3.4 
Digital Continuous and Triplicate 12-Lead ECG 
Digital continuous ECG monitoring (e.g., Holter monitor) will be used at the time points 
specified in Table 4 and Table 7. 
For all other time points where an ECG is required, computerized, good quality, 12-lead ECGs 
will be collected in triplicate and recorded. Recordings will be obtained in the supine position 
after the participant has rested comfortably for ≥5 minutes. If the initial reading is abnormal, the 
measurements will be repeated once to confirm the results. 
The ECG tracing will be read locally. In the case of clinically significant findings, an ECG may 
be further reviewed by a board-certified cardiologist for a second opinion. Information should be 
recorded as to whether the ECG is normal or abnormal and, if deemed abnormal, what the 
abnormality is, and whether it is clinically significant or not clinically significant. 
8.3.5 
Clinical Laboratory Evaluations 
Clinical laboratory safety testing, as detailed in Section 10.2 will be collected at the time points 
described in the SoA. Safety laboratory assessments will be conducted by a certified laboratory. 
If the initial reading is abnormal, the measurements will be repeated once to confirm the results. 

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When applicable and feasible, blood sampling should follow evaluation of vital signs and ECGs 
to reduce any impact on these measurements. 
8.3.6 
Pregnancy Testing 
For WOCBP, a serum pregnancy test will be done at Screening and at the final study visit or ET 
visit. Urine pregnancy tests will be done on Day -1 and at the visits noted in the SoA while on 
study. A positive urine pregnancy test will be confirmed, as soon as possible, with a serum 
pregnancy test. If a participant becomes pregnant while on study, refer to Section 10.3.6 for 
instructions on how this should be reported. 
8.4 
Adverse Events 
The definitions of AEs and SAEs and how they should be recorded, assessed, and reported can 
be found in Section 10.3. 
The Investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE, and remain responsible for following 
all ongoing AEs to the final study visit or ET visit, at a minimum, or until the Investigator and 
the Sponsor agree that further follow-up is not required. This includes events reported by the 
participant or, when appropriate, by a caregiver, surrogate, or the participant’s legally authorized 
representative. 
8.5 
Pharmacokinetic Assessments 
• Blood samples will be collected for measurement of plasma concentrations of WVE-006 
and for potential analysis of metabolites as specified in the SoA (Table 2 and Table 6). 
The actual date and time (24-hour clock time) of each sample will be recorded. 
Instructions for the collection and handling of biological samples will be provided by the 
Sponsor in a Laboratory Manual. 
• Plasma and urine samples for analysis of exposure to WVE-006 will be collected at the 
time points specified in Table 2, Table 3, and Table 6. Samples will be collected at the 
following time points: 
o Period 1 Plasma PK: Samples will be collected predose within 30 min prior to 
dose, and postdose at 30 min (±5 min), 1 hr (±5 min), 2 hr (±5 min), 4 hr (±10 
min), 6 hr (±10 min), 8 hr (±10 min), 12 hr (±10 min), 24 hr (±30 min), 36 hr (±4 
hr), and 48 hr (±4 hr). A sample will be collected at each of the following visits: 
Days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, 78 (±3 days), and Day 85 (±5 days)/ET. 
o Period 1 Urine PK: Samples will be collected over 0-4 hr, 4-8 hr, 8-12 hr, 
12-18 hr, 18-24 hr, 24-36 hr, and 36-48 hr. 
o Period 2 Plasma PK: Day 1 and Day 29 samples will be collected predose within 
30 min prior to dose, and postdose at 30 min (±5 min), 1 hr (±5 min), 2 hr 

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(±5 min), 4 hr (±10 min), 6 hr (±10 min), 8 hr (±10 min), 12 hr (±10 min), 24 hr 
(±30 min), 36 hr (±4 hr), and 48 hr (±4 hr). A Day 15 predose sample will be 
collected at 30 min prior to dose. A sample will be collected at each of the 
following visits: Days 8, 21, 36, 43, 50, 57, 64, 71, 78, 85 (±3 days) and Day 113 
(±5 days) / ET. 
• Urine samples will be collected for measurement of concentration of WVE-006 and 
potential metabolites as specified in the SoA (Table 3). The following parameters will be 
estimated for the parent drug: 
o Ae: amount excreted in urine 
o Ae%: the percentage of the administered dose that is excreted in urine 
o Cum Ae%: cumulative Ae% 
• The timing of sampling may be altered, and PK samples may be obtained at additional 
time points during the course of the study based on newly available data (e.g., to obtain 
data nearer the time of peak plasma concentration) to ensure appropriate monitoring of 
the PK profile. 
• Blood samples will be used to evaluate the PK profile of WVE-006 assessed by the 
following PK parameters, if applicable: 
o AUCinf: area under the curve from time 0 to infinity 
o AUC0-24h: area under the curve from time 0 to 24 hours 
o AUC0-48h: area under the curve from time 0 to 48 hours 
o AUClast: area under the curve from time 0 to the last measurable concentration 
o AUCext: area under the curve extrapolated to infinity 
o AUCtau: area under the curve over a dosing interval 
o Cmax: maximum observed concentration 
o tmax: time to occurrence of Cmax 
o t½: terminal half-life 
o Vd: volume of distribution 
o CL: clearance 
• Samples collected for analyses of WVE-006 plasma concentration may also be used to 
evaluate safety aspects arising during or after the study. 
• PK information that would unblind the study will not be reported to investigative sites or 
blinded personnel until the study has been unblinded. 
8.6 
Pharmacodynamic Assessments 
No PD assessments are included in this study. 

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8.7 
Genetics 
A blood sample for SERPINA1 AAT genetic testing will be collected from all participants at 
Screening. Participants who do not wish to participate in the AAT genetic research will not be 
able to participate in the study. 
Details on processes for collection, shipment, and destruction of these samples can be found in 
the Laboratory Manual. 
8.8 
Biomarkers 
Biomarkers are not evaluated in this study. 
8.9 
Immunogenicity Assessments 
Samples for antibodies to WVE-006 will be collected and may be analyzed in the future. 
8.10 Health Economics 
Health economics parameters are not evaluated in this study. 

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9 STATISTICAL CONSIDERATIONS 
The final analyses will be conducted on data collected from participants after the study database 
is locked at the end of the study. 
The statistical analysis plan will be created and finalized prior to the study database lock, and it 
will include more details of the planned statistical analysis for data that have been collected in 
this study. This section is a summary of the planned statistical analyses for the most important 
endpoints. 
9.1 
Sample Size Determination 
The sample size for this Phase 1 study on HV was not calculated on the basis of statistical 
hypothesis testing. However, the number of participants (up to 40 in the SAD period and 8 in the 
multiple-dose period) is considered sufficient for this study to assess safety and tolerability for 
WVE-006 and to establish PK profile of WVE-006. 
9.2 
Analysis Populations 
The following analysis sets will be defined for SAD and multiple-dose portions of the data 
analyses. 
• Safety population will include randomized participants who have received at least 1 dose 
of study medication. The safety population will be the analysis set used for summaries of 
safety data collected in the respective period. 
• PK population will consist of participants in the safety population with at least 1 post 
dose plasma concentration measurement. 
9.3 
Statistical Analyses 
9.3.1 
General Considerations 
Data collected in the SAD and multiple-dose periods will be summarized and reported separately 
by dose groups (e.g., a given dose cohort will be a dose group). For the SAD period, data from 
participants who received placebo will be pooled across cohorts and summarized and presented 
as the “Placebo” dose group, which will be handled as one of the dose groups throughout this 
section. 
Baseline for a SAD participant is defined as the last non-missing measurement collected prior to 
the administration of the single dose. Baseline for a multiple-dose participant is defined as the 
last non-missing measurement collected prior to the administration of study drug at Week 0 of 
multiple-dose period. Unless otherwise specified, the analyses described in the following 
sections apply to data collected in both SAD and multiple-dose periods. 

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Descriptive statistics (n, mean, standard deviation [SD], median, minimum and maximum values 
for continuous variables, and number and percentage of participants in each category for 
categorical variables) will be used for data summary by treatment group for each cohort. 
9.3.2 
Disposition of Participants 
Screened participants are defined as any participant who signed the ICF, and the number of 
screened participants will be summarized by dose group. 
Randomized participants consist of participants who signed the ICF and were subsequently 
randomly assigned. For each cohort, the number of randomized participants receiving placebo or 
WVE-006 will be tabulated. 
The number and percentage of participants who discontinued from the study along with the 
reasons of discontinuation will be summarized by dose group for the safety population. 
9.3.3 
Participants’ Demographics and Baseline Characteristics 
Participants’ demographics (age, gender, and race) and other baseline characteristics will be 
summarized by dose group for the safety population. 
9.3.4 
Study Drug Exposure and Compliance 
The number of participants who received study drug will be summarized by dose group, and 
compliance (for Period 2) will also be summarized for the safety population. 
9.3.5 
Analysis of Safety Data 
Safety analyses will be performed on the safety population. 
9.3.5.1 
Adverse Events 
• An AE is any untoward medical occurrence in a clinical study participant, temporally 
associated with the use of study drug, whether or not considered related to the study drug. 
• A treatment-emergent AE (TEAE) is defined as an AE not present before exposure to 
study treatment or any event already present that worsens in severity or frequency from 
the date of receiving first dose of study treatment to study completion or discontinuation. 
General rules of analysis and reporting of AEs: 
• AEs reported by Investigators will be coded to system organ class (SOC) and preferred 
term (PT) using the Medical Dictionary for Regulatory Activities (MedDRA). 
• For an event with multiple occurrences during the study, the event is only counted once 
in occurrence summary, the maximum severity is used when reporting the severity, the 
highest level of association will be used to characterize relatedness to study drug in 
reporting. 

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The number and percentage of participants who have at least a TEAE, a grade 3 or 4 TEAE, a 
study drug-related TEAE as judged by the Investigator will be summarized by dose group. In 
addition, the number and percentage of participants who have a TEAE that leads to study drug 
discontinuation or who died due to occurrence of a TEAE will also be summarized by dose 
group. The percentage for the aforementioned summaries will be calculated based on the number 
of participants in each dose group. 
 
For each dose group, TEAEs will be presented by PT with the descending frequency of 
occurrence based on the pooled WVE-006 dose groups. In addition, TEAEs will also be 
summarized by SOC, PT, and the severity for each dose group. 
The number and percentage of participants who had at least one SAE will be summarized by 
SOC and PT for each dose group. In addition, SAEs will be tabulated by dose group. 
9.3.5.2 
Analysis of Clinical Laboratory Evaluations, Vital Signs, and ECG 
Parameters 
For laboratory parameters, change from baseline to maximum or minimum value during the 
study will be summarized by dose group for each parameter and reported by laboratory group, 
respectively. In addition, changes from baseline to each post-baseline visit will also be 
summarized by dose group. 
Clinically significant changes will be summarized by dose group for vital signs. 
A shift table presenting the shift from baseline to each post-baseline assessment in terms of 
Normal or Abnormal by dose group will be used to report ECG findings during the study. 
9.3.6 
Pharmacokinetic Analysis 
PK data will be summarized descriptively and presented in both graphical and/or tabular formats. 
PK parameters for WVE-006 and potential metabolites will be calculated using non- 
compartmental methods. PK parameters will be summarized for each WVE-006 dose group on 
the PK population using descriptive statistics: n, arithmetic mean, median, SD, minimum, 
maximum, and percent coefficient of variation (CV%); in addition, the geometric mean and 
geometric CV% will be reported for Cmax and AUCs. 
The PK parameters described in Section 8.5 will be calculated for participants who receive at 
least one dose of WVE-006 during the study. Additional PK parameters may be evaluated if 
deemed necessary. 
When appropriate, the correlation between QTcF and WVE-006 will be evaluated, and the 
results may be reported separately from the Clinical Study Report. 

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When appropriate, the identification and quantification of WVE-006 and its metabolites in urine 
will be performed and the results may be reported in a separate report. 
9.3.7 
Interim Analyses 
No interim analyses are planned. 

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10 SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS 
10.1 Appendix 1: Regulatory, Ethical, and Study Oversight Considerations 
10.1.1 
Regulatory and Ethical Considerations 
• This study will be conducted in accordance with the protocol and with the following: 
− Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences (CIOMS) international ethical guidelines 
− Applicable ICH Good Clinical Practice (GCP) guidelines 
− Applicable laws and regulations 
• The protocol, protocol amendments, ICF, IB, and other relevant documents 
(e.g., advertisements) must be submitted to an IRB/EC by the Investigator and reviewed and 
approved by the IRB/EC before the study is initiated. 
• Any substantial amendments to the protocol will require IRB/EC approval before 
implementation of changes made to the study design, except for changes necessary to 
eliminate an immediate hazard to study participants. 
• Protocols and any substantial amendments to the protocol will require health authority 
approval prior to initiation except for changes necessary to eliminate an immediate hazard to 
study participants. 
• The Investigator will be responsible for the following, as applicable: 
− Providing written summaries of the status of the study to the IRB/EC annually or more 
frequently in accordance with the requirements, policies, and procedures established 
by the IRB/EC 
− Notifying the IRB/EC of SAEs or other significant safety findings as required by 
IRB/EC procedures 
− Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 Code of Federal Regulations (CFR), ICH guidelines, the IRB/EC, 
European regulation 536/2014 for clinical studies, European Medical Device 
Regulation 2017/745 for clinical device research, and all other applicable local 
regulations 
10.1.2 
Financial Disclosure 
Investigators and sub-investigators will provide the Sponsor with sufficient, accurate financial 
information as requested to allow the Sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators are 

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responsible for providing information on financial interests during the course of the study and for 
1 year after completion of the study. 
10.1.3 
Informed Consent Process 
• ICF templates will be provided to investigative sites. If any institution-specific 
modifications to study-related procedures are proposed or made by the site, the ICF(s) 
must be reviewed by the Sponsor or its designee or both before IRB/EC submission. 
Once reviewed, the ICF(s) will be submitted by the Investigator to his or her IRB/EC for 
review and approval before the start of the study. If the ICF(s) is revised during the 
course of the study, active participants must sign the revised form. 
• Before Screening, each prospective participant will be given a full explanation of the 
study and be allowed to read the approved ICF, as well as consult with others, as 
appropriate. 
• The Investigator or the Investigator’s qualified representative will explain the nature of 
the study, including the risks and benefits, to the potential participant and answer all 
questions regarding the study. 
• Once the Investigator is assured that the participant understands the implications of 
participating in the study, the participant will be asked to give consent to participate in 
the study by signing the appropriate ICF. 
• Potential participants must be informed that their participation is voluntary and that they 
will be required to sign a statement of informed consent. 
• The Investigator will use the approved ICF, which is intended to meet the requirements 
of 21 CFR 50, the Declaration of Helsinki, local regulations, ICH and GCP guidelines, 
privacy and data protection laws and regulations, as applicable, and the IRB/EC or study 
center. 
• The medical record must include a statement that written informed consent was obtained 
before the participant was enrolled in the study and the date the written consent was 
obtained. The authorized person obtaining the informed consent must also sign the ICF. 
• The ICF must be signed prior to conduct of any study-related activities for the 
participant. 
• Participants must be reconsented to the most current version of the ICF(s) during their 
participation in the study. 
• The Investigator will retain the signed original ICF(s). 
• A copy of the ICF(s) must be provided to the participant. 

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10.1.4 
Privacy and Data Protection 
10.1.4.1 
Privacy 
The Sponsor and Investigator(s) will ensure that this study is conducted in accordance with the 
most recent version of the applicable privacy laws, including local privacy laws. Additional 
information on how the Sponsor handles privacy can be found at 
https://wavelifesciences.com/privacy/. 
• Participants will be assigned a unique identifier by the Sponsor. Any participant records 
or datasets that are transferred to the Sponsor will contain the identifier only; participant 
names or any information which would make the participant identifiable will not be 
transferred. 
• The participant must be informed that their personal study-related data will be used by 
the Sponsor in accordance with local data protection law. The level of disclosure must 
also be explained to the participant who will be required to give consent for their data to 
be used as described in the ICF. 
• The participant must be informed that their medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the Sponsor, by 
appropriate IRB/EC members, and by inspectors from regulatory authorities, as 
applicable. 
• The contract between the Sponsor and study sites specifies responsibilities of the parties 
related to data protection, including handling of data security breaches and respective 
communication and cooperation of the parties. 
• Information technology systems used to collect, process, and store study-related data are 
secured by technical and organizational security measures designed to protect such data. 
10.1.5 
Committees Structure 
10.1.5.1 
Data Monitoring Committee 
An independent DMC composed of relevant medical experts and a statistician will be established 
to oversee study safety and recommend dose selection and escalation. DMC members will be 
unblinded. The DMC will oversee the overall safety of the study and will also provide input on 
dose escalation decisions along with the DEC (see Section 10.1.5.2). Details of the DMC such as 
composition, content (e.g., safety assessments to be summarized or listed) and frequency of data 
reports, and meeting frequency will be recorded in the DMC charter. 
10.1.5.2 
Dose Escalation Committee 
A DEC will be established to oversee dose selection and escalation decisions in Periods 1 and 2. 
The DEC will consist of the Investigator and blinded Sponsor representative. Details of the DEC 
such as composition and blinded data the DEC will require for each dose escalation decision will 
be recorded in the DEC charter. 

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10.1.6 
Dissemination of Clinical Study Data 
Whether the study is completed or terminated prematurely, the Sponsor will ensure that a final 
report is prepared and provided to the regulatory agency(ies), as applicable. The Sponsor will 
also ensure that the clinical study reports (CSRs) in marketing applications meet the standards of 
the ICH Guideline E3: Structure and Content of Clinical Study Reports. 
In accordance with local regulatory requirements, an Investigator will be identified for the 
approval and signoff of the clinical study report. The Investigator will be provided reasonable 
access to statistical tables, figures, and relevant reports and will have the opportunity to review 
the complete study results. 
10.1.7 
Data Quality Assurance 
• All participant data relating to the study will be recorded on the eCRFs unless transmitted 
to the Sponsor or designee electronically (e.g., laboratory data). The Investigator is 
responsible for verifying that data entries are accurate and correct by electronically 
signing the eCRF. 
• Guidance on completion of eCRFs will be provided in eCRF Completion Guidelines. 
• The Investigator must permit study-related monitoring, audits, IRB/EC review, and 
regulatory agency inspections and provide direct access to source documents. 
• Monitoring details describing strategy, including definition of study critical data items 
and processes (e.g., risk-based initiatives in operations and quality such as risk 
management and mitigation strategies and analytical risk-based monitoring), methods, 
responsibilities, and requirements, including handling of noncompliance issues and 
monitoring techniques (central, remote, or on-site monitoring) are provided in the 
monitoring plan and/or contracts. 
• The Sponsor or designee is responsible for the data management of this study, including 
quality checking of the data. 
• The Sponsor assumes accountability for actions delegated to other individuals (e.g., 
CROs). 
• Records and documents, including signed ICFs, pertaining to the conduct of this study 
must be retained by the Investigator for 2 years after the last approval of a marketing 
application in an ICH region and until there are no pending or contemplated marketing 
applications in an ICH region or at least 2 years have elapsed since the formal 
discontinuation of clinical development of the study drug unless local regulations or 
institutional policies require a longer retention period. No records may be destroyed 
during the retention period without the written approval of the Sponsor. No records may 
be transferred to another location or party without written notification to the Sponsor. 

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10.1.7.1 
Electronic Case Report Forms and Data Management 
Data will be entered directly from the source documents to the eCRFs within the 
Sponsor-provided EDC system following the eCRF Completion Guidelines. Source documents 
should be clear, complete, and accurate and should include all the details of study assessments 
performed per the protocol. The Investigator is responsible for ensuring the data entered on the 
eCRFs are accurate and complete and all data are entered in a timely manner. 
The final eCRF data and audit trails will be archived in an electronic media and placed in the 
Investigator’s study file. 
10.1.7.2 
Inspection of Records 
Investigators and institutions involved in the study will permit study-related monitoring, audits, 
IRB/EC review, and regulatory inspections by providing direct access to all study records, or as 
appropriate per local regulations. In the event of an audit, the Investigator agrees to allow the 
Sponsor, representatives of the Sponsor, or regulatory authorities access to all study records. 
The Investigator should notify the Sponsor promptly of any audits scheduled by any regulatory 
authorities and will promptly forward copies of any audit reports to the Sponsor. 
10.1.8 
Source Documents 
• Source documents provide evidence for the existence of the participant and substantiate 
the integrity of the data collected. Source documents are filed at the Investigator’s site. 
• Data entered in the eCRF that are transcribed from source documents must be consistent 
with the source documents or the discrepancies must be explained. Current medical 
records must be available. 
• Definition of what constitutes source data and its origin can be found in the monitoring 
plan. 
• The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF. 
• The Sponsor or designee will perform monitoring to confirm that data entered into the 
eCRF by authorized site personnel are accurate, complete, and verifiable from source 
documents; that the safety and rights of participants are being protected; and that the 
study is being conducted in accordance with the currently approved protocol and any 
other study agreements, ICH GCP, and all applicable regulatory requirements. 
10.1.9 
Study and Site Start and Closure 
First Act of Recruitment 
The first act of recruitment is the signing of the first ICF and will be the study start date. 

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Study/Site Termination 
The Sponsor or designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the Sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study-site closure visit has been performed. 
The Investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure by the Sponsor or Investigator may include but are not limited to: 
• For study termination: 
− Discontinuation of further study drug development 
• For site termination: 
− Failure of the Investigator to comply with the protocol, the requirements of the 
IRB/EC or local health authorities, the Sponsor’s procedures, or GCP guidelines 
− Inadequate or no recruitment (evaluated after a reasonable amount of time) of 
participants by the Investigator 
If the study is prematurely terminated or suspended, the Sponsor shall promptly inform the 
Investigators, the IRBs/ECs, the regulatory authorities, and CROs used in the study of the reason 
for termination or suspension, as specified by the applicable regulatory requirements. The 
Investigator shall promptly inform the participant and should assure appropriate participant 
therapy and/or follow-up. 
Upon completion or termination of the study, the study monitor will conduct site closure 
activities with the Investigator or site staff (as appropriate), in accordance with applicable 
regulations, ICH GCP, and SOPs. 
10.1.10 
Publication Policy 
All information regarding WVE-006 supplied by the Sponsor to the Investigator or generated as 
a result of any clinical studies is privileged and confidential information belonging to the 
Sponsor. The Investigator agrees to use Sponsor’s confidential information solely to accomplish 
the study and will not use or publish such information for any other purposes without the prior 
written consent of the Sponsor. The Investigator is obligated to provide the Sponsor with 
complete and accurate data obtained during the study. The information obtained from the clinical 
study will be used toward the development of WVE-006 and may be disclosed by the Sponsor to 
regulatory authority(ies), other Investigators, corporate partners, and consultants as required. 
It is anticipated that the results of this study may be presented at scientific meetings and/or 
published in a peer-reviewed scientific or medical journal. The Investigator may publish results 
from the study in compliance with their agreements with the Sponsor. A pre-publication 

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manuscript is to be provided to the Sponsor at least 45 days prior to the submission of the 
manuscript to a publisher. 

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10.2 Appendix 2: Clinical Laboratory Tests 
• The tests detailed in Table 11 will be performed per the Sponsor provided Laboratory 
Manual. 
• Laboratory tests will be done at the time points per the SoA in Section 1.3. Urine dipstick 
and urine pregnancy test results will be recorded in the participant’s medical record and 
corresponding eCRFs. 
• Protocol-specific laboratory value requirements for inclusion or exclusion of participants 
are detailed in Section 5 of the protocol. 
• Additional tests may be performed at any time during the study as determined necessary 
by the Investigator or required by local regulations. 
• Investigators must document their review of each laboratory safety report. Any laboratory 
result considered by the Investigator as clinically significant must be documented as AE 
and graded per CTCAE criteria. (see Section 10.3). 
Table 11 
Detailed Clinical Laboratory Tests 
 
Laboratory Tests 
Parameters 
Hematology1 
• Platelet count 
• Red blood cell (RBC) count 
− 
RBC indices 
− Mean corpuscular volume (MCV) 
− Mean corpuscular hemoglobin (MCH) 
− Mean corpuscular hemoglobin 
concentration (MCHC) 
− %Reticulocytes 
• White blood cell (WBC) count with 
differential: 
− Neutrophils 
− Lymphocytes 
− Monocytes 
− Eosinophils 
− Basophils 
• Hemoglobin 
• Hematocrit 
• Markers of Inflammation 
− C-reactive protein 
− Complement (C3, Bb, C3a, and sC5b9) 
Clinical chemistry2 
• Blood urea nitrogen (BUN) 
• Potassium 
• Creatinine 
• Sodium 
• Gamma glutamyl transferase 
• Chloride 
• Bicarbonate 
• Blood glucose 
• Aspartate transaminase (AST) 
• Alanine transaminase (ALT) 
• Alkaline phosphatase 
• Total Bilirubin (direct bilirubin if Total 
Bilirubin is elevated) 
• Creatine phosphokinase 
• Total protein 
• Albumin1 
• Glutamate dehydrogenase (GLDH) 

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Coagulation1 
• Prothrombin time or international normalized ratio (INR) (per site’s laboratory standards) 
• Activated partial thromboplastin time (aPTT) 
• Fibrinogen 
Routine urinalysis 
• Specific gravity, pH, glucose, protein, blood, ketones, bilirubin, urobilinogen 
− 
If abnormal findings (excluding trace) by dipstick or urinalysis are noted, urine 
microscopy is required 
Pregnancy testing 
• FSH testing will be conducted at baseline if needed to confirm WOCBP status. 
• Highly sensitive serum or urine human chorionic gonadotropin (hCG) pregnancy test (as 
needed, for women of childbearing potential) 
Other screening 
tests 
• SERPINA1 genotyping 
• Alcohol breath or urine test 
• Cotinine 
• Drug screen, which will include: 
− 
Amphetamines 
− 
Methamphetamines 
− 
Methadone 
− 
Barbiturates 
− 
Benzodiazepines 
− 
Cocaine 
− 
Opiates 
− 
Methylenedioxymethamphetamine 
− 
Phencyclidine 
− 
Tetrahydrocannabinol 
• Serology (HIV antibody, C-19 [if applicable], hepatitis B surface antigen [HBsAg], 
hepatitis C virus antibody,). If hepatitis B or C serology is positive, the following reflex 
testing should be done: 
− 
Hepatitis B: total anti-HBc, IgM anti-HBc, and anti-HBs 
− 
Hepatitis C: HCV-RNA 
NOTES: 
1. Refer to Table 2 and Table 6 for specific time points at which these laboratory assessments are required. 

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10.3 Appendix 3: AEs and SAEs: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting 
An AE is defined as any untoward medical occurrence in a participant enrolled into this study 
regardless of its causal relationship to study treatment. Participants will be instructed to contact 
the Investigator at any time after enrolling if any symptoms develop. 
The Investigator is responsible for reporting all AEs that are observed or reported during the 
study, regardless of their relationship to study treatment or their clinical significance. 
AE information will be collected beginning at enrollment (time of signed ICF) and up to the end 
of the study. All ongoing AEs at the end of the study will be followed to resolution, stabilization, 
or until the Investigator and the Sponsor agree that further follow-up is not required. 
A TEAE is defined as any new AE that begins following study drug treatment that was not 
present before exposure to study drug treatment or any condition already present that worsens in 
either intensity or frequency after exposure to study drug treatment. 
10.3.1 
Eliciting and Documenting Adverse Events 
All AEs reported or observed during the study will be recorded on the AE page in the eCRF and 
in the site source notes. The eCRFs used to document AEs are designed to help ensure this 
information is collected in a standard way. Information to be collected includes AE term, date 
and time of onset, date and time of resolution, Investigator-specified assessment of severity and 
relationship to study treatment, action taken with respect to study treatment, seriousness, any 
required treatment or evaluations, and outcome. For AEs of injection site reactions, additional 
information will be collected in the eCRF and source document. The sites will be provided with 
completion guidelines for the eCRF, which will further guide them on how to record the data, 
including AEs. MedDRA will be used to code all AEs. 
In addition to observations of the participant, AEs identified from any study data (e.g., laboratory 
values, physical examination findings, ECG changes) or identified from review of other 
documents that are considered clinically significant will be documented on the AE page in the 
eCRF. 
AEs will be assessed at each visit by direct questioning from site staff, as well as elicited from 
physical examination by site staff (when applicable). In addition, all sites in the study must 
ensure participants have a 24-hour telephone number to contact medical site staff for the duration 
of the study in case of emergent AEs or SAEs. 
If there is any doubt as to whether a clinical observation is an AE, the event should be reported. 
10.3.2 
Time Period and Frequency for Collecting AE and SAE Information 
AEs and SAEs will be collected beginning with the signing of the ICF until the last study visit or 
ET visit. 

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Medical occurrences that begin before the start of study drug but continue after obtaining 
informed consent will be recorded as medical history/current medical conditions, not as AEs 
unless the condition has worsened in terms of severity or frequency. 
Investigators are not obligated to actively seek information on AEs after conclusion of study 
participation. SAEs that occur after the final follow-up visit need not be reported unless the 
Investigator considers them at least possibly related to study drug. However, if the Investigator 
learns of any pregnancy within a month after a participant completed or was discharged from the 
study, the Investigator must promptly notify the Sponsor (see Section 10.3.6). 
10.3.3 
Follow-up of AEs and SAEs 
After the initial AE, the Investigator is required to follow each participant at subsequent 
visits/contacts. AEs will be followed until resolution, stabilization, the event is otherwise 
explained, the final study visit, or the participant is lost to follow-up (as defined in Section 7.3). 
10.3.4 
Definitions of Adverse Event Severity and Relationship to Study Drug 
10.3.4.1 
Severity 
The severity or intensity of an AE refers to the extent to which an AE affects the participant’s 
daily activities. AE severity (except for injection site reactions, covered in Section 10.6) will be 
evaluated using the criteria outlined in National Cancer Institute (NCI)-CTCAE Version 5.0 to 
determine its severity. The full reference can be found at: 
https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/CTCAE_v5_Quick_R 
eference_8.5x11.pdf. 
Table 12 
NCI-CTCAE General Grading Criteria 
 
Grade 
AE Severity 
Definition 
1 
Mild 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated. 
2 
Moderate 
Moderate; minimal, local or noninvasive intervention indicated. 
3 
Severe 
Severe or medically significant but not immediately life-threatening; hospitalization or 
prolongation of hospitalization indicated; disabling; limiting self-care. 
4 
Life-threatening 
Life-threatening consequences; urgent intervention indicated. 
5 
Death 
Death related to AE. 
Abbreviations: AE = adverse event; CTCAE = Common Terminology Criteria for Adverse Events; NCI = National 
Cancer Institute. 
Note: the most applicable grading criteria should be used based on the nature of the AE, and this table should 
be used if none of the specific criteria match the AE. 
 
Changes in the severity of an AE should be documented in the eCRF to allow an assessment to 
be performed related to the duration of the event at each level of intensity. 

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10.3.4.2 
Relationship to Study Drug 
The Investigator’s assessment of an AE’s relationship to study treatment is part of the 
documentation process. All AEs, regardless of relationship, will be recorded in the eCRF. In 
addition, SAEs will be reported to regulatory authorities as required by local regulation 
(Section 10.3.5.4). 
The relationship or association of the study drug in causing or contributing to the AE will be 
characterized using the following classification and criteria presented in Table 13. 
Table 13 
Guidelines for Determining the Relationship (if any) Between 
Adverse Event and the Study Drug 
 
AE Relationship 
Definition 
Definite 
This relationship suggests that a definite causal relationship exists between treatment 
administration and the AE, and that other conditions (concurrent illness, 
progression/expression of disease state, or concurrent medication reaction) do not 
appear to explain the event. The event reappears or worsens if the study treatment is 
re-administered. 
Probable 
This relationship suggests that a reasonable temporal sequence of the event with 
treatment administration exists, and, based upon the known pharmacological action of 
the treatment, known or previously reported adverse reactions to the treatment or class 
of treatment, or judgment based on the Investigator’s clinical experience, the 
association of the event with the study treatment seems likely. The event disappears or 
decreases on cessation of study treatment. 
Possible 
This relationship suggests that the study treatment caused or contributed to the AE, i.e., 
the event follows a reasonable temporal sequence from the time of treatment 
administration or follows a known response pattern to the study treatment but could 
also have been caused by alternative factors. 
Unlikely Related 
This relationship suggests an improbable (but not impossible) association between the 
study medication and the reported event. 
Not Related 
This relationship suggests no association between the study treatment and the reported 
event. 
Abbreviations: AE=adverse event. 
 
10.3.5 
Serious Adverse Events 
10.3.5.1 
Serious Adverse Events Criteria 
An SAE is defined as any event that results in: 
• Death 
• Is immediately life-threatening. A life-threatening event does not include an AE that if it 
had occurred in a more severe form, might have caused death. 
• Requires inpatient hospitalization or prolongation of existing hospitalization 
• Results in persistent or significant disability/incapacity 

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• Is a congenital anomaly 
• Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered SAEs when they, based upon appropriate medical 
judgment, may jeopardize the participant or may require medical or surgical intervention 
to prevent one of the outcomes listed in this definition. Examples of such medical events 
include allergic bronchospasm requiring intensive treatment in an emergency room or at 
home, blood dyscrasias or convulsions that do not result in inpatient hospitalization, or 
the development of drug dependency or drug abuse. 
Any hospital admission with at least one overnight stay will be considered an inpatient 
hospitalization. However, emergency department visits that do not result in overnight 
hospitalization would only be considered an SAE if they meet other SAE criteria (e.g., important 
medical event). Admission to the hospital for social or situational reasons (e.g., no place to stay, 
long distance for hospital visits, etc.) will not be considered as meeting hospitalization criteria 
for defining an SAE. 
Hospitalization for an elective or outpatient procedure for a pre-existing condition will not be 
considered as an SAE and should be captured under procedures in the eCRF. However, 
unexpected complications and/or prolongation of hospitalization during elective 
surgery/procedure should be reported as an SAE. 
Serious AEs must be reported within 24 hours; any updated SAE data will also be reported 
within 24 hours of it being available. SAEs that occur after the final follow-up visit need not be 
reported unless the Investigator considers them at least possibly related to study drug. 
10.3.5.2 
Suspected Unexpected Serious Adverse Reaction 
A suspected unexpected serious adverse reaction (SUSAR) is an SAE for which there is a 
reasonable possibility that the study drug caused the event, and this SAE has not been previously 
identified as an expected/listed AE. A list of expected AEs (if applicable) is provided in the 
current version of the IB and is considered the Reference Safety Information (RSI) for the study. 
Generally, the indication for which a product is intended would not be on the list of expected 
serious adverse reactions (SAR), but if it did occur, would not be considered “unexpected” for 
SUSAR reporting. As an example, a flare-up of symptoms consistent with the underlying disease 
under treatment that required hospitalization would constitute a SAR; however, the event would 
not be considered unexpected. An exception would be if the reporter believed that study drug 
worsened the underlying condition. 
10.3.5.3 
Serious Adverse Event Follow-up 
Appropriate remedial measures should be taken by the Investigator using his/her best medical 
judgment to treat the SAE. These measures and the participant’s response to these measures 
should be recorded. All SAEs, regardless of relationship to study drug, will be followed by the 
Investigator until resolution or stabilization. Clinical, laboratory, and diagnostic measures should 
be employed by the Investigator as needed to adequately determine the etiology of the event. 

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10.3.5.4 
Serious Adverse Event Reporting 
10.3.5.4.1 
Reporting Requirements 
Any AE that meets SAE criteria must be reported to the Sponsor and/or designee immediately 
(i.e., within 24 hours) after the time site personnel first learn about the event using the SAE 
Report Form provided for the study. Regardless of causality, all SAEs must be reported and will 
be collected and recorded from the time the participant/legal guardian signs the ICF until 
completion of the final follow-up visit. All SAEs must also be recorded in the participant’s 
source documentation and on the AE page of the participant’s eCRF. 
The initial report should include at least the following information: 
• Study number 
• Participant’s identification number 
• Description of the event 
• Date and time of onset of the event 
• Seriousness criteria 
• Causality assessment to study drug 
If follow-up is obtained or requested by the Sponsor and/or designee, the additional information 
should be emailed on an SAE Report Form to the Sponsor in a timely manner according to the 
procedures and timelines outlined above. Copies of discharge summaries, consultant reports, 
autopsy reports, and any other relevant documents may also be requested. 
The Investigator will be responsible for reporting all SAEs to the IRB or EC. The Sponsor will 
be responsible for reporting to the regulatory authorities and Central Ethics Committees, as per 
local requirements. 
An Investigator who receives an Investigator Safety Report describing an SAE or other specific 
safety information (e.g., summary or listing of SAEs) from the Sponsor will review and file it 
along with the IB and will notify the IRB/EC, if appropriate according to local requirements. 
10.3.5.4.2 
SAE Contact Information 
Current SAE contact information can be found in the Study Manual. 
10.3.6 
Pregnancies 
If a participant becomes pregnant during the study, she must be discontinued from study drug 
and monitoring of the participant and fetus should be conducted until the pregnancy outcome is 
known. The Investigator should notify the Medical Monitor, and a Pregnancy Notification Form 
should be completed. At the completion of the pregnancy, the Investigator will document the 
outcome of the pregnancy. 

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If a male participant’s partner becomes pregnant during the study, the same reporting and 
monitoring requirements will apply, but the partner must first consent to being followed. 
If the Investigator becomes aware of a pregnancy up to a month after participant’s completion of 
the study, the pregnancy will be reported to the Sponsor’s Medical Monitor and followed up as 
described above. 
Pregnancy in and of itself is not an SAE. Complications of the pregnancy that meet seriousness 
criteria (e.g., hospitalization) should be reported to the Sponsor within 24 hours of knowledge by 
the Investigator (i.e., if the mother is hospitalized for dehydration) and an SAE form must be 
completed. In addition, if the pregnancy ends for any reason before the anticipated date, the 
Investigator should notify the Sponsor. If the outcome of the pregnancy meets the criteria for 
immediate classification as an SAE (i.e., postpartum complication, spontaneous abortion, 
stillbirth, neonatal death, or congenital anomaly), the Investigator should follow the procedures 
for reporting an SAE. 

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10.4 Appendix 4: Contraceptive and Barrier Guidance 
Participants who are sexually mature and sexually active must be willing to use contraception as 
noted in Section 10.4.2 from 
 prior to Day 1 through 
 after the last dose of study 
drug for females and from Day 1 through 
 after the last dose of study drug for males. If 
site requirements for contraception are more stringent, the site requirement will be followed. 
Of note, men or women exclusively engaging in same-sex sexual activities are not required to 
use contraception. 
10.4.1 
Definitions 
10.4.1.1 
Non-Childbearing Potential 
A woman of non-childbearing potential is defined in criterion 9 of Section 5.1. 
If a female participant’s child-bearing potential is uncertain in the Investigator’s opinion, FSH 
testing will be conducted at Screening (see Table 1 and Table 5). 
10.4.2 
Highly Effective Methods of Contraception 
Contraception methods that can achieve a failure rate of <1% per year when used consistently 
and correctly are considered highly effective. Such methods include: 
• Combined (estrogen and progestogen containing) hormonal contraception associated with 
inhibition of ovulation: 
− Oral 
− Intravaginal 
− Transdermal 
• Progestogen-only hormonal contraception associated with inhibition of ovulation: 
− Oral 
− Injectable 
− Implantable 
• Intrauterine device (IUD) 
• Intrauterine hormone-releasing system (IUS) 
• Bilateral tubal ligation 
• Vasectomized sole partner (for a participant who is a WOCBP) 
 
For male participants only: 
• Condom, with or without spermicide, or 
• At least 3 months following successful vasectomy 
CCI
CCI
CCI

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10.5 Appendix 5: Management of Protocol Amendments and Deviations 
10.5.1 
Modification of the Protocol 
Changes in this research activity, except those necessary to remove an apparent, immediate 
hazard to the participant, must be reviewed and approved by the Sponsor or designee. 
Amendments to the protocol must be submitted in writing to the Investigator’s IRB/EC and 
regulatory authorities for approval before participants can be enrolled into an amended protocol. 
10.5.2 
Protocol Deviations 
A deviation from the protocol is any change, divergence, or departure from the study design or 
procedures defined in the protocol and associated manuals, ICF, recruitment process, or study 
materials approved by the Sponsor, Investigator, and the IRB/EC. 
Important protocol deviations are a subset of protocol deviations that might significantly affect 
the completeness, accuracy, and/or reliability of the study data or that might significantly affect a 
participant's rights, safety, or well-being. For example, important protocol deviations might 
include enrolling participants in violation of key eligibility criteria designed to ensure a specific 
study population or failing to collect data necessary to interpret primary endpoints, as this may 
compromise the scientific value of the study. 
All processes and procedures defined in this protocol must be adhered to. Emergency departures 
from the protocol that eliminate an apparent immediate hazard to a particular participant and that 
are deemed by the Investigator as crucial for the safety and well-being of that participant may be 
instituted for that participant only and documented as deviations. The Investigator will contact 
the Medical Monitor as soon as possible regarding such a deviation. These departures do not 
require preapproval by the IRB/EC; however, the IRB/EC and Medical Monitor must be notified 
in writing as soon as possible in accordance with the IRB/EC policies after the departure has 
been made. 
Protocol deviations will be documented by the clinical monitor in the clinical study management 
system and on monitoring reports throughout the course of monitoring visits. Investigators will 
be notified in writing by the monitor of deviations. As required by local regulatory authorities, 
the Investigator will notify the IRB/EC of any applicable protocol deviations in a timely manner. 
No protocol deviations to eligibility, also known as waivers, will be permitted. 

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A Phase 1, Randomized, Double-Blind, Placebo-Controlled Study in Healthy Participants 
WVE-006 
Confidential 
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10.6 Appendix 6: Grading of Injection Site Reactions 
Individual signs or symptoms (e.g., erythema, swelling, etc.) at the injection site reported by a 
participant following study drug administration will be recorded as an injection site reaction and 
as an AE if grade 1 or more. 
 
Grading of Injection Site Reactions (FDA, 2007) 
 
Local Reaction to 
Injectable Product 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Potentially Life 
Threatening 
(Grade 4) 
Pain 
Does not 
interfere 
with activity 
Repeated use 
of non-narcotic 
pain reliever 
>24 hours or 
interferes with 
activity 
Any use of 
narcotic pain 
reliever or 
prevents daily 
activity 
Emergency room 
(ER) visit or 
hospitalization 
Tenderness 
Mild 
discomfort 
to touch 
Discomfort 
with 
movement 
Significant 
discomfort at 
rest 
ER visit or 
hospitalization 
Erythema/Redness 
2.5 – 5 cm 
5.1 – 10 cm 
>10 cm 
Necrosis or 
exfoliative 
dermatitis 
Induration/Swelling* 
2.5 – 5 cm 
and does not 
interfere 
with activity 
5.1 – 10 cm or 
interferes with 
activity 
>10 cm or 
prevents daily 
activity 
Necrosis 
* Induration/Swelling should be evaluated and graded using the functional scale, as well as the actual measurement. 

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A Phase 1, Randomized, Double-Blind, Placebo-Controlled Study in Healthy Participants 
WVE-006 
Confidential 
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