Clinical trial NCT04617847
Conditions: Huntington Disease
Sponsor: Wave Life Sciences Ltd.
Start date: 2020-04-13; Completion date: 2021-05-03
Enrollment: 27 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
WVE-HDSNP1-002 is an open-label extension (OLE) study to evaluate the safety, tolerability, PK, PD, and clinical effects of WVE-120101 in adult patients with early manifest HD who carry a targeted single nucleotide polymorphism, rs362307 (SNP1). To participate in the study, patients must have completed the Phase 1b/2a clinical study WVE-HDSNP1-001.

Detailed description:

Arms: arm 1: None
Interventions: intervention 1: WVE-120101
Intervention descriptions: intervention 1: WVE-120101 is a stereopure antisense oligonucleotide (ASO). It is administered monthly via intrathecal injection.

Protocol documents:
Prot_SAP_000.pdf: 


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CLINICAL PROTOCOL APPROVAL FORM 
Sponsor: Wave Life Sciences 
I have read and understand the contents of this clinical protocol for Study No. 
WVE‑HDSNP1‑002 dated 31 March 2020 and agree to meet all obligations of the Sponsor as 
detailed in all applicable regulations and guidelines. In addition, I will inform the Principal 
Investigator and all other Investigators of all relevant information that becomes available 
during the conduct of this Study. 


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PRINCIPAL INVESTIGATOR’S AGREEMENT 
I have read and understand the contents of this clinical protocol for Study No. 
WVE‑HDSNP1‑002 dated 31 March 2020 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 Food and Drug Administration (FDA) regulations, and other 
local regulatory requirements: 
Name of Principal Investigator: 
Title: 
Institution: 
Address: 
Phone:  
Fax:  
 
 
 
Signature 
 
Date 
 


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PROTOCOL SYNOPSIS 
Sponsor: 
Investigational 
Product: 
Developmental 
Phase: 
EudraCT Number: 
Wave Life Sciences  
WVE-HDSNP1-002 
Phase 1b/2a 
2019-003637-42 
Title of Study: A Multicenter, Open-label Extension (OLE) Study to Evaluate the Safety, Pharmacodynamics, 
and Clinical Effects of WVE-120101 in Patients with Huntington’s Disease 
Protocol Number: WVE-HDSNP1-002 
Study Center(s): Approximately 25 study sites worldwide 
Objectives:  
Primary objective: 
• 
To evaluate the safety and tolerability of long-term exposure to WVE-120101 in patients with early 
manifest Huntington’s disease (HD)  
Secondary objectives: 
• 
To evaluate the clinical and pharmacodynamic (PD) effects of WVE-120101 in patients with early 
manifest HD 
Exploratory Objectives: 
• 
To evaluate the pharmacokinetics (PK) of WVE-120101 in plasma  
• 
To evaluate WVE-120101 related excretion in urine 
• 
To evaluate the exposure of WVE-120101 in cerebrospinal fluid (CSF) 
• 
To evaluate the effect of WVE-120101 on exploratory biomarkers  
Methodology: This is an open-label extension (OLE) study to evaluate the safety, tolerability, PK, PD, and 
clinical effects of WVE-120101 in adult patients with early manifest HD who carry a targeted single 
nucleotide polymorphism, rs362307 (SNP1). The planned duration of this study is approximately 101 weeks. 
To participate in the study, patients must have completed their Day 168 or 196 visit (depending upon dosing 
cohort and requirements in a given country) of the Phase 1b/2a clinical study WVE‑HDSNP1‑001.  
Screening may last up to 4 weeks. Patients will be dosed on Day 1 with WVE-120101 administered via the 
intrathecal (IT) route. Patients will return to the clinic every 4 weeks for dosing visits and safety monitoring. 
Every 12 weeks, patients will undergo assessments of clinical effects. After the last dosing visit (Week 97), 
patients will return for 1 follow-up safety visit at Week 101.  
Dose Modifications 
In the original OLE study protocol, patients who were in the 2 and 4 mg dose cohorts in the Phase 1b/2a study 
were enrolled into the 4 or 8 mg dose group in this study. Patients who were in the 8 and 16 mg dose cohorts in 
the Phase 1b/2a study were enrolled into the 8 or 16 mg dose groups, respectively in this study. As of this 
amendment, patients will receive 16 mg or a higher dose of WVE-120101 in this study. The maximum dose 
and frequency in this OLE study in a given country will not exceed the maximum dose and frequency 
described in the Phase 1b/2a protocol (WVE-HDSNP1-001) approved in that country. If a dose lower than the 
maximum dose described in the Phase 1b/2a study is chosen for multiple dosing based on the safety review of 
the Phase 1b/2a study data by the Dose Escalation Committee (DEC) and Safety Monitoring Committee 
(SMC), that dose will be used in this OLE study.  
Based on the SMC and DEC review of Phase 1b/2a safety data, the highest tolerated dose level and/or a lower 
dose level may be selected for multiple dosing and further evaluation in the OLE. If one dose level is selected, 
all patients will be switched to receive treatment at that dose level. If more than one dose is selected, patients 
will be randomized 1:1 to the highest tolerated dose and one lower dose to be determined by the DEC in 


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Sponsor: 
Investigational 
Product: 
Developmental 
Phase: 
EudraCT Number: 
Wave Life Sciences  
WVE-HDSNP1-002 
Phase 1b/2a 
2019-003637-42 
agreement with the SMC. The randomization will be stratified by cohort and use a fixed block size. These 
doses may be further revised based on emerging safety, PD, or clinical effects data in the Phase 1b/2a study. 
The maximum dose and frequency in this OLE study will not exceed the maximum dose and frequency 
described in the Phase 1b/2a protocol (WVE-HDSNP1-001) approved in each country. 
Dose modification will occur at the next scheduled visit from the date of implementation of this amendment 
(Amendment 1.0). In addition to the assessments performed at every dosing visit, the Unified Huntington’s 
Disease Rating Scale (UHDRS) and clinical laboratory evaluations should be performed at the visit when a 
dose is changed. 
Number of Patients (Planned): Approximately 50 patients will be enrolled. 
Study Population: Patients must satisfy all of the inclusion and none of the exclusion criteria to be eligible for 
the study.  
Inclusion Criteria: 
1. Patient has documented ability to understand the written study informed consent forms (ICFs) at the time 
of screening and has provided signed written informed consent prior to any study procedures.  
2. Patient successfully completed their Day 168 or 196 visit (depending upon dosing cohort and requirements 
in a given country) of the Phase 1b/2a study with WVE-120101, WVE-HDSNP1-001. 
3. In the opinion of the Investigator, the patient is able to tolerate all study procedures, is willing to comply 
with all other protocol requirements, and tolerated study drug in the parent study. 
4. Patient is willing to practice highly effective contraception for the duration of the study if the patient or 
their partner are of childbearing potential. Non-childbearing potential and highly effective methods of 
contraception are defined in the protocol (Section 5.2.1.1).  
Exclusion Criteria 
1. Clinically significant medical finding on the physical examination other than HD that, in the judgment of 
the Investigator, will make the patient unsuitable for participation in and/or completion of the study 
procedures. 
2. Received an investigational drug other than WVE-120101, including an investigational oligonucleotide, 
within the past 1 year or 5 half-lives of the drug, whichever is longer. 
3. Implantable central nervous system (CNS) device that may interfere with ability to administer study drug 
via lumbar puncture or undergo brain magnetic resonance imaging (MRI) scan. 
4. Diagnostic and Statistical Manual of Mental Disorders 5th Edition (DSM-5) diagnosis at the Screening 
Visit of active alcohol, cannabinoid, or other substance use disorder (except nicotine). 
5. Positive for opioids (unprescribed), cocaine, amphetamines, methadone, barbiturates, methamphetamine, 
or phencyclidine at the Screening Visit.  
6. Pregnant (as determined by a serum pregnancy test) or breast feeding at the Screening Visit, or plans to 
become pregnant during the course of the study. 
7. Clinically significant laboratory abnormality at Screening, including, but not limited to: 
a. 
Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) values at Screening or Baseline 
>3 times the upper limit of normal (ULN). 
b. Renal insufficiency, defined as either serum creatinine >1.8 mg/dL or creatinine clearance 
<40 mL/min. 
8. Clinically significant abnormality at Screening electrocardiogram (ECG), including but not limited to a 
confirmed QT interval corrected for heart rate (QTc) ≥450 msec for males or ≥470 msec for females. 


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Sponsor: 
Investigational 
Product: 
Developmental 
Phase: 
EudraCT Number: 
Wave Life Sciences  
WVE-HDSNP1-002 
Phase 1b/2a 
2019-003637-42 
9. Clinically significant cardiovascular, endocrine, hepatic, renal, pulmonary, gastrointestinal, neurologic, 
malignant, metabolic, psychiatric, or other condition that, in the opinion of the Investigator, precludes the 
patient’s safe participation in the study or would interfere with the study assessments.  
10. Bone, spine, bleeding, or other disorder that exposes the patient to risk of injury or unsuccessful lumbar 
puncture. 
11. Inability to undergo brain MRI (with or without sedation).  
12. In the opinion of the Investigator, deemed to be at significant risk for suicidal behavior. 
13. Involved directly or indirectly in the conduct and administration of this study as an Investigator, sub-
investigator, study coordinator, or other study staff member, or the patient is a first-degree family member, 
significant other, or relative residing with one of the above persons involved directly or indirectly in the 
study. 
14. Anticipates using antiplatelet or anticoagulant therapy during the course of the study. Patients who 
received antiplatelet or anticoagulant therapy must complete one of the following washout periods before 
the Screening Visit:  
a. 
A 7-day washout period for antiplatelet therapy, 
b. A 1-day washout period for anticoagulants (except warfarin), or 
c. 
A 5-day washout period for warfarin. 
Investigational Product, Dose, Route, Regimen: WVE-120101. Patients will receive ≥16 mg (not to exceed 
the maximum dose and frequency described in the Phase 1b/2a protocol (WVE-HDSNP1-001) approved in 
each country). The investigational product will be supplied as a lyophilized powder that will be reconstituted 
into an injectable solution. The route of administration of the reconstituted WVE-120101 solution will be IT 
injection by direct lumbar puncture.  
Reference Therapy, Dose, Route, Regimen: Not applicable. All patients will receive WVE-120101. 
Study Duration: The planned duration is 101 weeks. Patients will receive doses every 4 weeks over a period 
of 97 weeks, then complete a safety follow-up phase. 
Endpoints:  
Safety Endpoints: 
The number of patients with adverse events (AEs), severity of AEs, number of patients with serious AEs 
(SAEs), clinically significant changes in laboratory values, and the number of patients who withdraw due to 
AEs. 
Clinical Effects Endpoint(s): 
 
Change from baseline in the Total Functional Capacity (TFC), administered as part of the Unified 
Huntington’s Disease Rating Scale (UHDRS) 
 
Change from baseline in the motor, cognitive, independence, and functional assessments administered 
as part of the UHDRS 
 
Change from baseline in the composite UHDRS (cUHDRS)  
 
Change from baseline in the Short Problem Behaviors Assessment (PBA-s) 
Pharmacodynamic Endpoints: 
 
Change from baseline in the concentration of mutant huntingtin (mHTT) protein in CSF 
 
Changes from baseline MRI of the brain 


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Sponsor: 
Investigational 
Product: 
Developmental 
Phase: 
EudraCT Number: 
Wave Life Sciences  
WVE-HDSNP1-002 
Phase 1b/2a 
2019-003637-42 
 
Change from baseline in exploratory biomarkers, including but not limited to neurofilament light 
(NFL) 
PK Endpoints: 
 
PK parameters of WVE-120101 in plasma  
 
WVE-120101 and WVE-120101-related metabolite excretions in urine 
 
Concentration of WVE-120101 in CSF  
Statistical Methods:  
Sample size determination 
No sample size calculations were performed. As this is an OLE, the maximum sample size is fixed by the 
number of patients completing the WVE-HDSNP1-001 study. 
Analysis populations 
The safety population will include all enrolled patients who have received at least one dose of study 
medication in the OLE. The safety population analysis set will be used for summaries of safety and clinical 
effects.  
The per-protocol population will be a subset of the safety population and include patients with no major 
protocol deviations that will interfere with the assessment of the clinical effects endpoints and with at least 
80% compliance to the dosing regimen. 
The PK population will consist of all patients in the safety population with at least one post-dose plasma or 
CSF concentration measurement. 
Analysis of safety 
The primary objective of this OLE is to evaluate the safety of WVE-120101. The safety analysis will be 
descriptive and will include summaries of treatment-emergent AEs (TEAEs), TEAEs leading to treatment 
discontinuation, TEAEs by severity, TEAEs by relationship, and serious TEAEs. Changes in laboratory 
assessments will also be summarized. 
Analysis of Clinical Effects and PD 
The change from baseline for clinical effects and PD endpoints will be summarized using a mixed model for 
repeated measures (MMRM) with the safety population. The MMRM will be used to construct 95% 
confidence intervals and to test if the change is statistically significant.  
 
 
 


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TABLE OF CONTENTS 
Title Page ............................................................................................................................1 
Clinical Protocol Approval Form .....................................................................................2 
Principal Investigator’s Agreement .................................................................................3 
Protocol Synopsis ...............................................................................................................4 
Table of Contents ...............................................................................................................8 
List of Appendices ............................................................................................................10 
List of Tables ....................................................................................................................10 
List of Figures ...................................................................................................................11 
List of Abbreviations .......................................................................................................12 
1 
Introduction...............................................................................................................14 
1.1 
Disease Background .............................................................................................14 
1.2 
Investigational Product WVE-120101................................................................14 
1.3 
Nonclinical Data ...................................................................................................15 
1.4 
Clinical Experience ..............................................................................................16 
2 
Rationale for the Study ............................................................................................17 
2.1 
Rationale for the Doses, the Dosing Regimen, and Route of Administration 17 
3 
Study Objectives .......................................................................................................18 
4 
Study Design ..............................................................................................................19 
4.1 
Study Design Overview........................................................................................19 
4.1.1 
Screening Phase ..............................................................................................20 
4.1.2 
Treatment Phase ............................................................................................21 
4.1.3 
Follow-Up Visit...............................................................................................22 
4.1.4 
Early Treatment Withdrawal and Early Termination...............................22 
4.2 
Schedule of Assessments ......................................................................................22 
4.3 
Study Endpoints ...................................................................................................28 
4.4 
Safety Monitoring Committee Reviews .............................................................28 
5 
Patient Selection and Withdrawal Criteria ............................................................29 
5.1 
Inclusion Criteria .................................................................................................29 
5.2 
Exclusion Criteria ................................................................................................29 
5.2.1 
Additional Study Restrictions .......................................................................30 
5.3 
Withdrawal and Discontinuation .......................................................................31 
5.3.1 
Withdrawal of Patient from the Study.........................................................31 
5.3.2 
Discontinuation of Study Treatment ............................................................32 
5.3.3 
Lost to Follow-up ...........................................................................................32 
5.3.4 
Replacements ..................................................................................................32 
6 
Investigational Drug .................................................................................................33 
6.1 
Method of Assigning Patients to Investigational Drug .....................................33 
6.2 
Dose and Investigational Drug Administration ................................................33 
6.2.1 
Identity of Investigational Drug ...................................................................33 
6.2.2 
Administration of Investigational Drug .......................................................33 
6.3 
Treatment Compliance ........................................................................................34 
6.4 
Management of Clinical Supplies .......................................................................34 
6.4.1 
Investigational Drug Packaging and Storage ..............................................34 
6.4.2 
Investigational Drug Accountability ............................................................34 


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6.4.3 
Other Supplies ................................................................................................34 
7 
Blinding And Randomization ..................................................................................35 
8 
Methods of Assessment and Endpoints ...................................................................35 
8.1 
Safety Assessments ...............................................................................................35 
8.1.1 
Medical History and Demographics .............................................................35 
8.1.2 
Prior and Concomitant Medications ............................................................36 
8.1.3 
Physical Examination ....................................................................................36 
8.1.4 
Vital Signs .......................................................................................................37 
8.1.5 
Height and Weight .........................................................................................37 
8.1.6 
12-Lead ECG ..................................................................................................37 
8.1.7 
Clinical Laboratory Evaluations ..................................................................37 
8.1.8 
Cerebrospinal Fluid Safety Lab ...................................................................38 
8.1.9 
Suicidality Assessment (Columbia-Suicide Severity Rating Scale) ...........38 
8.1.10 
Pregnancy Testing ..........................................................................................38 
8.1.11 
Drug Screening ...............................................................................................38 
8.2 
Pharmacokinetic Assessments ............................................................................39 
8.3 
Pharmacodynamic Assessments .........................................................................39 
8.4 
Immunogenicity Assessments .............................................................................39 
8.5 
Magnetic Resonance Imaging .............................................................................39 
8.6 
Assessment of Clinical Effects.............................................................................40 
8.6.1 
Unified Huntington’s Disease Rating Scale .................................................40 
8.6.2 
Short Problem Behaviors Assessment ..........................................................41 
9 
Adverse Events ..........................................................................................................41 
9.1 
Eliciting and Documenting Adverse Events ......................................................41 
9.2 
Definitions of Adverse Event Severity and Relationship to Study Drug ........42 
9.2.1 
Severity............................................................................................................42 
9.2.2 
Relationship to Study Drug ...........................................................................42 
9.3 
Serious Adverse Events .......................................................................................43 
9.3.1 
Serious Adverse Event Criteria ....................................................................43 
9.3.2 
Suspected, Unexpected, Serious Adverse Reaction .....................................44 
9.3.3 
Serious Adverse Event Follow-up.................................................................44 
9.3.4 
Serious Adverse Event Reporting.................................................................44 
9.4 
Overdose ...............................................................................................................45 
9.5 
Pregnancies ...........................................................................................................45 
10 Statistical Considerations .........................................................................................46 
10.1 
Sample Size Determination .................................................................................46 
10.2 
Disposition of Patients .........................................................................................46 
10.3 
Analysis Populations ............................................................................................46 
10.4 
Statistical Methods ...............................................................................................46 
10.4.1 
Study Drug Exposure and Compliance........................................................46 
10.4.2 
Analysis of Safety Data ..................................................................................47 
10.4.3 
Pharmacokinetic Analyses ............................................................................48 
10.4.4 
Clinical Effects and Pharmacodynamic Analyses .......................................49 
11 Regulatory, Ethical, and Legal Obligations ...........................................................49 
11.1 
Declaration of Helsinki ........................................................................................49 




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LIST OF FIGURES 
Figure 1 
Schematic of Study Design ......................................................................19 
Figure 2 
Dose Modification Scheme ......................................................................20 
 


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LIST OF ABBREVIATIONS  
Abbreviation 
Definition 
3T 
3 Tesla 
AE 
adverse event 
ALT 
alanine aminotransferase 
aPTT 
activated partial thromboplastin time 
ASO 
antisense oligonucleotide 
AST 
aspartate aminotransferase 
AUC0-τ  
area under the plasma concentration-time curve over the dosing interval  
AUClast 
area under the plasma concentration-time curve from time 0 to the last measured time 
point  
C 
Celsius  
CAG 
cytosine-adenine-guanine 
CFR 
Code of Federal Regulations 
Cmax 
maximum observed concentration 
CNS 
central nervous system 
CSF 
cerebrospinal fluid 
CSR 
clinical study report 
C-SSRS 
Columbia Suicide Severity Rating Scale 
cUHDRS 
composite Unified Huntington’s Disease Rating Scale  
DEC 
Dose Escalation Committee 
DNA 
deoxyribonucleic acid 
DSM-5 
Diagnostic and Statistical Manual of Mental Disorders 5th Edition 
EC 
Ethics Committee 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EDC 
electronic data capture 
EHDN 
European Huntington’s Disease Network 
ET 
early termination 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HD 
Huntington’s disease 
HED 
human equivalent dose  
HTT, HTT 
Huntingtin gene or huntingtin protein 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
INN 
International Nonproprietary Name 


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Abbreviation 
Definition 
IRB 
Institutional Review Board 
IT 
intrathecal 
IUD 
intrauterine device  
IUS 
intrauterine hormone-releasing system 
IXRS 
interactive voice/web response system 
MedDRA 
Medical Dictionary for Regulatory Activities 
mHTT, mHTT 
mutant huntingtin gene or protein 
MMRM 
mixed model for repeated measures 
MRI 
magnetic resonance imaging 
mRNA 
messenger ribonucleic acid 
NFL  
neurofilament light  
OLE 
Open-label extension 
PBA-HD 
Problem Behaviors Assessment for HD 
PBA-s 
Short Problem Behaviors Assessment 
PD 
Pharmacodynamic(s) 
PK 
Pharmacokinetic(s) 
PS 
phosphorothioate 
PT 
prothrombin time 
QTc 
QT interval corrected for heart rate 
RNA 
ribonucleic acid 
RSI 
reference safety information 
SAE 
serious adverse event 
SDMT 
Symbol Digit Modalities Test 
SMC 
Safety Monitoring Committee 
SNP 
single nucleotide polymorphism 
SNP1 
single nucleotide polymorphism rs362307 
SOC 
system organ class 
SOP 
Standard Operating Procedure 
SUSAR 
suspected unexpected serious adverse reaction 
TEAE 
treatment-emergent adverse event 
TFC 
Total Functional Capacity 
tmax 
time of occurrence of Cmax 
U 
uracil 
UHDRS 
Unified Huntington’s Disease Rating Scale 
ULN 
upper limit of normal 
wtHTT 
wild-type huntingtin 


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1 INTRODUCTION 
WVE-120101 is intended as a disease-modifying agent for the treatment of patients with 
Huntington’s disease (HD). It is a stereopure antisense oligonucleotide (ASO) intended to 
selectively target the mutant form of the huntingtin (mHTT) gene transcript at the uracil (U) 
variant of single nucleotide polymorphism (SNP) rs362307 (SNP1).  
1.1 
Disease Background 
Huntington’s disease is a rare, progressive neurological disease that results in motor, cognitive, 
and psychiatric disability and is invariably fatal1.  Because it is a genetic, hereditary disease, it 
can affect multiple family members across generations2.  Although cognitive and psychiatric 
symptoms may develop first, the clinical diagnosis of HD is usually based on the presence of 
chorea, one of the most visually prominent symptoms of this disease.  Chorea is an abnormal 
involuntary movement disorder, which occurs in 90% of patients and is moderate to severe in 
approximately 70% of these patients.  These physical symptoms can appear at any age, but 
typically appear between the ages of 30 and 501.  A physical examination, sometimes combined 
with a neurological examination, can determine whether the onset of the disease has begun.  Life 
expectancy after symptom onset is reduced to around 15 to 20 years1,2.  Prevalence in Europe, 
North America, and Australia is approximately 6 per 100,0003.  In the United States alone, 
approximately 30,000 people have diagnosed HD4,5 and another 200,000 or more Americans 
carry the gene and are at risk of developing the disease5.  Currently, no treatments exist that can 
cure, slow, or reverse the course of HD.  Some of the symptoms of HD can be managed with 
medication and therapies such as antipsychotics and drugs that affect the dopamine pathways, 
which modulate the movement disorder2. 
Huntington’s disease is caused by known mutations in a single gene, that are characterized by an 
expansion of a cytosine-adenine-guanine (CAG) triplet repeat in the Huntingtin (HTT) gene6.  
Wild-type HTT (wtHTT) protein is critical for neuronal development7.  Although the purpose of 
wtHTT in adults is not completely understood, some studies have shown that it may play an 
important role in neuronal functions7-10.  However, expansion in the CAG triplet repeat in the 
HTT gene results in production of the mHTT protein.  Accumulation of this protein leads to 
progressive loss of neurons in the brain2.  In nonclinical studies, lowering the level of mHTT 
protein as measured in the cerebrospinal fluid (CSF) has been demonstrated to be therapeutic11,12.  
Therefore, a drug that can silence the mHTT gene transcript, while leaving the wild-type allele 
intact, may be able to slow down, stop, or even reverse the course of HD13. 
1.2 
Investigational Product WVE-120101 
WVE-120101 is an oligonucleotide, a type of nucleic acid that includes innovative drugs that are 
assembled from chemically modified, short-length ribonucleic acid (RNA) or deoxyribonucleic 
acid (DNA) strands. The potential therapeutic uses of oligonucleotides include modulating the 
function of target RNAs to affect the production of disease-associated proteins. The mechanism 
of action used by many oligonucleotides, including ASOs, is to promote degradation of the target 
RNA. Phosphorothioate (PS) modification was one of the earliest and remains one of the most 


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common backbone modifications used in oligonucleotide synthesis. These modifications 
improve the stability, biodistribution, and cellular uptake of oligonucleotides. The use of PS 
modification in oligonucleotide synthesis creates a chiral center at the phosphorus of each PS, 
which has either an “Sp” or “Rp” configuration at random. A conventional, fully PS-modified 
oligonucleotide (20 nucleotides in length, 19 PS modifications) is a mixture of over 500,000 
stereoisomers (219), each having the same nucleotide sequence but differing in the 
stereochemistry along its backbone, resulting in heterogenous and uncontrolled pharmacological 
properties. 
The Sponsor has developed PRISM™, a proprietary technology that enables the synthesis of 
PS-modified nucleic acid therapeutics in which stereochemistry at each PS position is precisely 
controlled. This degree of control enables rational design and synthesis of optimized, or 
stereopure, oligonucleotides with improved pharmacological and toxicological properties as 
compared to stereorandom molecules. 
WVE-120101 specifically targets the mHTT messenger ribonucleic acid (mRNA) transcript, at 
the U variant of SNP1. A SNP is a single variation in the DNA that can be associated with a 
mutated gene. One of the most frequent SNPs in the mHTT gene is SNP1, which has been shown 
to be present in approximately 50% of patients with HD13-16.    
1.3 
Nonclinical Data 
The nonclinical program evaluating WVE-120101 encompasses in vitro studies of primary and 
secondary pharmacology, in vitro and in vivo genetic toxicology, and in vivo safety 
pharmacology and toxicity studies.  
In vitro pharmacology studies confirm that WVE-120101 demonstrates selective knockdown of 
the mHTT messenger ribonucleic acid (mRNA) and protein through cleavage of the mRNA 
transcript of the mutant allele with the targeted single nucleotide polymorphism (SNP) rs362307 
(SNP1) versus the wild type allele.  This selective knockdown results in greater reduction of the 
mHTT protein over wild type huntingtin (wtHTT) protein produced by this ribonucleic acid 
(RNA) and, thus, limits the unintended, potentially deleterious effects of decreasing wtHTT7-
10.  In vivo tissue distribution studies in animals demonstrate that, upon intrathecal (IT) 
administration, WVE-120101 distributes to the brain, the intended target tissue where it may be 
able to produce sustained and effective target suppression of mtHTT.  However, in the absence 
of an animal model recapitulating the mutation observed in this subpopulation of HD patients, no 
in vivo data are available regarding the concentration required to reduce the level of mHTT in 
vivo or the potential duration of knockdown.  The optimal dose and dosing frequency for 
efficacy in humans will be explored during clinical development. 
In vitro, WVE-120101 is highly protein-bound in rat, monkey, and human plasma (>99%).  
Following single or multiple monthly intrathecal (IT) administrations of WVE-120101 in rats 
and monkeys, dose dependent increases were observed in plasma, central nervous system (CNS), 
and systemic tissues (kidney, liver, and spleen). Systemic accumulation of WVE-120101 after 
repeated dosing was minimal. No in vitro cytochrome P450 (CYP) inhibition or induction was 
observed at clinically relevant concentrations of WVE-120101. 


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In single and repeat-dose IT studies in rats and monkeys, transient, dose-dependent limb 
dysfunction was observed. In rats findings were observed at dose levels of 0.1 mg (human 
equivalent dose [HED] 56 mg) in a single-dose study and 0.05 mg (HED 28 mg) and above in 
repeat doses. These findings resolved within 72 hours. In monkeys, findings were observed at 
doses up to 6 mg (HED 67.2 mg). Over the course of 9 months in a chronic toxicity study in 
monkeys, affected animals at doses ≤2 mg experienced only 1 or 2 instances of limb dysfunction 
at sporadic time points. In monkeys, only the lower hind limbs were affected and findings were 
completely resolved within 48 hours post-dose. Due to their transience, lack of correlating 
histopathology, and lack of effect on the ability of animals to eat or ambulate, the findings were 
considered non-adverse. 
Microscopic CNS findings were observed in both rats and monkeys after IT administration of 
WVE-120101. In rats, after 3 months of repeat IT dosing, cellular infiltrates, minimal to mild 
non-adverse spinal nerve root degeneration, and gliosis were observed. The findings were dose- 
and/or dose-concentration dependent, with minimal effects observed at 0.05 mg (dose 
concentration 2 mg/mL).  In monkeys, after 3 to 9 months of repeat IT dosing, minimal to mild 
(3-month study) or minimal to moderate (9-month study) mononuclear cell infiltrates were 
observed at all doses evaluated.  These findings were considered manifestations of the injection 
procedure and a general response to the immune-stimulating properties of the oligonucleotide17,18 
and were considered non-adverse.  
WVE-120101 demonstrated minimal potential for class effects associated with phosphorothioate 
oligonucleotides, such as systemic pro-inflammatory effects, activated partial thromboplastin 
time (aPTT) prolongation, hepatotoxicity, and nephrotoxicitiy18,19.  In addition, WVE-120101 
was not associated with any other toxicities, including mutagenicity or effects on cardiovascular 
or respiratory function, and WVE-120101 exhibited minimal potential for off-target effects via 
bioinformatic analysis of the human genome.    
In an vivo genotoxicity study in rats, a statistically significant but non-dose-related increase in 
micronucleated polychromatic erythrocytes was observed in rats. This increase was not 
considered biologically meaningful, since the values were within the historical control range for 
the test facility and anti-kinetochore staining demonstrated that the findings were not the result of 
an aneugenic mechanism. Moreover, because WVE-120101 was negative in an in vitro panel of 
genotoxicity studies; there were no histological findings in long-term animal studies suggestive 
of effects on dividing cells; and because oligonucleotides are not known to carry a genotoxic 
risk; WVE-120101 is unlikely to induce genotoxic effects under the proposed conditions of use.   
Based on the results of the nonclinical studies, the risk/benefit for further investigation of WVE-
120101 as a disease-modifying agent for the treatment of patients with HD is acceptable. Further 
details on the nonclinical experience with WVE-120101 can be found in the current version of 
the Investigator’s Brochure (IB).   
1.4 
Clinical Experience 
WVE-120101 is currently being evaluated in a Phase 1b/2a multicenter, randomized, double-
blind, placebo-controlled study to evaluate the safety, tolerability, pharmacokinetics (PK), and 


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pharmacodynamics (PD) of single and multiple doses of IT WVE-120101 in adult patients with 
early manifest HD who carry a targeted single SNP, SNP1 (WVE-HDSNP1-001).  
In the Phase 1b/2a study, as of the last data cutoff at single doses up to 16 mg (20 March 2020) 
and multiple doses up to 4 mg (02 March 2020), no stopping criteria have been observed. No 
related SAEs or related TEAEs associated with the HLGT Spinal Cord and Nerve Root 
Disorders have been reported. No clinically meaningful trends in hematology, coagulation, or 
chemistry values followed dosing. Final data are not yet available from this study. An 
independent Safety Monitoring Committee (SMC) will continue to review safety data from study 
WVE-HDSNP1-001 on an ongoing basis. The SMC will also review data for this OLE study in 
conjunction to the data from the Phase 1b/2a study to inform decisions in dose escalation and 
continuation of multiple dosing. If any stopping rules are met in the Phase 1b/2a study, or if the 
SMC decides to stop the Phase 1b/2a study for any other reason, those decisions will also apply 
to this study. More detailed information is provided in the Investigator’s Brochure. 
2 RATIONALE FOR THE STUDY 
This open-label extension (OLE) study is being conducted to evaluate the safety, tolerability and 
clinical effects of monthly IT doses of WVE-120101 over 97 weeks. Patients must complete 
their Day 168 or 196 visit (depending upon dosing cohort and requirements in a given country) 
of the prior Phase 1b/2a clinical study (WVE-HDSNP1-001) to be eligible for screening for this 
extension study.  
2.1 
Rationale for the Doses, the Dosing Regimen, and Route of Administration 
This is an open-label extension study for the Phase 1b/2a clinical study WVE-HDSNP1-001. The 
clinical starting dose in WVE-HDSNP1-001 was selected in consideration of the data from both 
single- and 13-week repeat-dose toxicology studies; an animal model possessing the SNP1 
variant targeted by WVE-120101 was not available to the Sponsor. The clinical starting dose of 2 
mg was based on the no-adverse-effect-level (NOEL) for transient limb dysfunction in monkeys, 
which is considered the most relevant species for the purposes of clinical assessment. The lack of 
findings in the monkey at a dose of 2 mg provides a 10-fold safety margin to the HED, on the 
basis of relative CSF volume. Subsequent doses are selected based on safety assessments from 
each cohort. 
In the original OLE study protocol, patients who were in the 2 and 4 mg dose cohorts in the 
Phase 1b/2a study were enrolled into the 4 or 8 mg dose group in this study. Patients who were in 
the 8 and 16 mg dose cohorts in the Phase 1b/2a study were enrolled into the 8 or 16 mg dose 
groups, respectively in this study. As of this amendment, patients will receive 16 mg or a higher 
dose of WVE-120101 in this study. The maximum dose and frequency in this OLE study in a 
given country will not exceed the maximum dose and frequency described in the Phase 1b/2a 
protocol (WVE-HDSNP1-001) approved in that country. If a dose lower than the maximum dose 
described in the Phase 1b/2a study is chosen for multiple dosing based on the safety review of 
the Phase 1b/2a study data by the Dose Escalation Committee (DEC) and Safety Monitoring 
Committee (SMC), that dose will be used in this OLE study.  


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Based on the SMC and DEC review of Phase 1b/2a safety data, the highest tolerated dose level 
and/or a lower dose level may be selected for multiple dosing and further evaluation in the OLE. 
If one dose level is selected, all patients will be switched to receive treatment at that dose level. 
If more than one dose is selected, patients will be randomized 1:1 to the highest tolerated dose 
and one lower dose to be determined by the DEC in agreement with the SMC. The 
randomization will be stratified by cohort and use a fixed block size. These doses may be further 
revised based on emerging safety, PD, or clinical effects data in the Phase 1b/2a study. The 
maximum dose and frequency in this OLE study will not exceed the maximum dose and 
frequency described in the Phase 1b/2a protocol (WVE-HDSNP1-001) approved in each country. 
For more details on additional dose modifications refer to Section 4.1.    
At the time when the Phase 1b/2a study is completed, the dose and dose interval in this OLE 
study may be further adjusted. A final determination about the optimal dose and dose-frequency 
will be made on the basis of data from the WVE-HDSNP1-001 study. It is possible that patients 
will be up-titrated or down-titrated depending on the dose they were receiving at the time of that 
decision. Up- or down-titration of the dose will only occur at the cohort level, not on an 
individual patient level.  
The follow-up period will continue to Week 101, 4 weeks after the last dose. Based on PK data 
from animal studies, the plasma half-life of WVE-120101 is less than 24 hours and the potential 
for accumulation is low. Clinical data from the ongoing WVE-HDSNP1-001 study show that 
adverse events tend to occur within the first week or two after dosing. A 4-week follow-up 
period after the last dose is therefore considered a sufficient period of time to observe potential 
adverse events.  
3 STUDY OBJECTIVES 
Primary Objective: 
The primary objective of this study is to evaluate the safety and tolerability of long-term 
exposure to WVE-120101 in patients with early manifest HD.  
Secondary Objectives: 
The secondary objectives of this study are to evaluate the clinical and pharmacodynamic effects 
of WVE-120101 in patients with early manifest HD.  
Exploratory Objectives: 
The exploratory objectives are: 
 To evaluate the PK of WVE 120101 in plasma  
 To evaluate WVE-120101 related excretion in urine 
 To evaluate the exposure of WVE-120101 in CSF 


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 To evaluate the effect of WVE-120101 on exploratory biomarkers 
4 STUDY DESIGN 
4.1 
Study Design Overview 
This is an OLE study to evaluate the safety, tolerability, PK, PD, and clinical effects of WVE-
120101 in adult patients with early manifest HD who carry a targeted single nucleotide 
polymorphism, SNP1. The planned duration of this study is approximately 101 weeks. To 
participate in the study, patients must have completed their Day 168 or 196 (depending upon 
dosing cohort and requirements in a given country) of the parent Phase 1b/2a clinical study 
WVE-HDSNP1-001.  
Screening may last up to 4 weeks. Patients will be dosed on Day 1 with WVE-120101 
administered via the IT route and stay in the clinic for monitoring through 4 hours postdose.  
Patients will return to the clinic every 4 weeks for dosing visits and safety monitoring. Every 12 
weeks, patients will undergo assessments of clinical effects. After the last dosing visit (Week 
97), patients will return for 1 follow-up safety visit at Week 101.  
A schematic of the overall study design and timing is provided in Figure 1. 
Figure 1 
Schematic of Study Design 
 
Dose Modifications 
In the original OLE study protocol, patients who were in the 2 and 4 mg dose cohorts in the 
Phase 1b/2a study were enrolled into the 4 or 8 mg dose group in this study. Patients who were in 
the 8 and 16 mg dose cohorts in the Phase 1b/2a study were enrolled into the 8 or 16 mg dose 
groups, respectively in this study. As of this amendment, patients will receive 16 mg or a higher 
dose of WVE-120101 in this study (Figure 2). The maximum dose and frequency in this OLE 
study in a given country will not exceed the maximum dose and frequency described in the Phase 
1b/2a protocol (WVE-HDSNP1-001) approved in that country. If a dose lower than the 
maximum dose described in the Phase 1b/2a study is chosen for multiple dosing based on the 
safety review of the Phase 1b/2a study data by the Dose Escalation Committee (DEC) and Safety 
Monitoring Committee (SMC), that dose will be used in this OLE study.  


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Based on the SMC and DEC review of Phase 1b/2a safety data, the highest tolerated dose level 
and/or a lower dose level may be selected for multiple dosing and further evaluation in the OLE. 
If one dose level is selected, all patients will be switched to receive treatment at that dose level. 
If more than one dose is selected, patients will be randomized 1:1 to the highest tolerated dose 
and one lower dose to be determined by the DEC in agreement with the SMC (Figure 2). The 
randomization will be stratified by cohort and use a fixed block size. These doses may be further 
revised based on emerging safety, PD, or clinical effects data in the Phase 1b/2a study. The 
maximum dose and frequency in this OLE study will not exceed the maximum dose and 
frequency described in the Phase 1b/2a protocol (WVE-HDSNP1-001) approved in each country. 
Dose modification will occur at the next scheduled visit from the date of implementation of this 
amendment (Amendment 1.0). In addition to the assessments performed at every dosing visit, the 
Unified Huntington’s Disease Rating Scale (UHDRS) and clinical laboratory evaluations should 
be performed at the visit when a dose is changed. Patients will not be asked to restart the 
treatment phase but will continue to receive doses as originally scheduled, every 4 weeks, at the 
new dose level.  
Figure 2 
Dose Modification Scheme 
 
Abbreviations: DEC=Dose Escalation Committee; SMC=Safety Monitoring Committee 
*Dose modification randomization. Applicable if 2 doses are studied.  
4.1.1 
Screening Phase 
The screening period is intended to allow determination of patient eligibility for the study. 
Screening will begin when the study informed consent form (ICF) is signed.  
The patient must sign a study ICF on Day 1 of Screening. The ability of the patient to understand 
the consent form will be documented in the study ICF.   
The Screening tests and evaluations must be completed within 4 weeks prior to enrollment. The 
required screening evaluations are outlined in the Schedule of Assessments (Table 1). Applicable 
evaluations from the last in-clinic visit in the Phase 1b/2a study WVE-HDSNP1-001 may be 
used if the last in-clinic visit occurred within 4 weeks prior to the Screening visit for this study 
(specified in Table 1). Screening assessments can occur over multiple days, provided they are 
within the Screening period. The Investigator will determine whether the patient meets eligibility 
criteria and will collect the demographic and medical data permitting full characterization of the 
patient. In addition, the Investigator should discuss the need for a legally authorized 
representative to provide consent on behalf of the patient in the event that the patient’s cognitive 
capacity deteriorates during the course of the OLE study to the point that they are no longer able 
to consent.  In addition, patients should identify a study partner (Section 4.1.1.1). These may or 
may not be the same person. 


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4.1.1.1 
Study Partner 
Patients should identify a study partner for the purposes of this trial. The role of the study partner 
will be to help ensure that the patient complies with study visits and assessments. Patients should 
have the same study partner throughout the course of the trial. The study partner must sign an 
acknowledgement of responsibilities form. The study partner does not have to be a legally 
authorized representative. 
4.1.2 
Treatment Phase 
WVE-120101 will be administered monthly via IT dosing through Week 97. At each visit, 
patients will be evaluated for safety and tolerability. At the end of each 12-week period, patients 
will undergo assessments of clinical effects. A schedule of assessments is provided in Table 1.  
Up to 1 week before performing lumbar puncture for each dose, a blood sample will be tested 
locally for platelet count and prothrombin time to confirm that it is safe to proceed with the 
lumbar puncture (Section 8.1.7). Other predose assessments may also be performed up to 1 week 
before dosing as specifically listed in Table 1. 
At all dosing visits, patients should be monitored for a minimum of 4 hours postdose in the 
clinic. After the first dose only, a follow-up safety phone call will be performed on Day 2.  
Immediately after study drug administration, all patients should be ambulatory for approximately 
30 minutes postdose. Formal physical examinations targeting the neurological system will be 
performed at the time points noted in the Schedule of Assessments (Table 1).  
Patients who are entering the study may be requested to consent to two additional lumbar 
punctures (LP) to provide CSF samples at two weeks after the first dose, and two weeks after the 
sixth dose to allow for more robust PK/PD modeling (see Table 1 for more details). These 
additional CSF samples will be optional, and consent will be collected as a stand-alone question 
in the Informed Consent Form. If a patient has already passed the first dose, but not the sixth, 
and is willing to undergo the additional LP, then CSF will be collected 2 weeks after the sixth 
dose.  
In addition to the above two CSF samples, patients at certain participating sites will undergo 
additional intensive PK blood and urine sampling as noted in Table 2. This sampling will include 
additional time points for plasma and a 24-hour urine collection. 
Dose Modifications 
In the original OLE study protocol, patients who were in the 2 and 4 mg dose cohorts in the 
Phase 1b/2a study were enrolled into the 4 or 8 mg dose group in this study. Patients who were in 
the 8 and 16 mg dose cohorts in the Phase 1b/2a study were enrolled into the 8 or 16 mg dose 
groups, respectively in this study. As of this amendment, patients will receive 16 mg or a higher 
dose of WVE-120101 in this study. The maximum dose and frequency in this OLE study in a 
given country will not exceed the maximum dose and frequency described in the Phase 1b/2a 


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protocol (WVE-HDSNP1-001) approved in that country. If a dose lower than the maximum dose 
described in the Phase 1b/2a study is chosen for multiple dosing based on the safety review of 
the Phase 1b/2a study data by the Dose Escalation Committee (DEC) and Safety Monitoring 
Committee (SMC), that dose will be used in this OLE study.  
Based on the SMC and DEC review of Phase 1b/2a safety data, the highest tolerated dose level 
and/or a lower dose level may be selected for multiple dosing and further evaluation in the OLE. 
If one dose level is selected, all patients will be switched to receive treatment at that dose level. 
If more than one dose is selected, patients will be randomized 1:1 to the highest tolerated dose 
and one lower dose to be determined by the DEC in agreement with the SMC. The 
randomization will be stratified by cohort and use a fixed block size. These doses may be further 
revised based on emerging safety, PD, or clinical effects data in the Phase 1b/2a study. The 
maximum dose and frequency in this OLE study will not exceed the maximum dose and 
frequency described in the Phase 1b/2a protocol (WVE-HDSNP1-001) approved in each country. 
For more details on additional dose modifications see Section 4.1.  
4.1.3 
Follow-Up Visit 
All patients are required to complete follow-up assessments, including evaluations of safety, PD, 
PK, and clinical effects (Table 1). Patients will be followed until Week 101 (4 weeks after the 
last dose). An early termination (ET) visit will be required in the event of early withdrawal.  
4.1.4 
Early Treatment Withdrawal and Early Termination  
If a patient withdraws from treatment, but wishes to remain in the study, the patient should 
continue with all planned visits and applicable assessments. PK assessments as well as lumbar 
punctures (with associated labs) will no longer be necessary unless a patient agrees to allow for 
one final lumbar puncture. A urine pregnancy test should be completed on the visit after the last 
dose of treatment.    
If a patient withdraws from the study, the patient should complete an early termination visit 
(Table 1).  
4.2 
Schedule of Assessments 
The schedule of assessments is provided in Table 1. The schedule of additional assessments for 
patients undergoing intensive PK assessments is provided in Table 2. 
 


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Table 1 
Schedule of Assessments 
Timing of 
Assessment (Visit 
Window, if 
applicable) 
Event/Assessment 
Screeninga 
Treatment 
Follow-up 
ET 
Wk -4 to 
Wk -1 
Wk 1 
Wk 5 
(±3 
days) 
Wks  
(±1 
Wk) 
Wks  
(±1 
Wk) 
Wks  
(±1 
Wk) 
Wk 97  
(±1 
Wk) 
Dose 
Modification 
Assessmentsb 
Additional 
CSF 
Collectionc 
(Optional) 
Wk 101  
(±1 Wk) 
9 
13 
25 
17, 21 
29, 33 
37 
49 
41, 45 
53, 57 
61 
73 
Day -28 to 
Day -1 
Day 1 
Day 2d 
65, 69 
77, 81 
85 
89, 93 
Patient ICF signed 
X 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
Drug screening 
X 
 
 
 
 
 
 
 
 
 
 
 
Medical history and 
demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
C-SSRSe,f  
X 
X 
 
X 
X 
X 
X 
X 
 
 
X 
X 
UHDRSe,f 
 
X 
 
X 
 
X 
X 
X 
X 
 
X 
X 
PBA-se,f 
 
X 
 
X 
X 
X 
X 
X 
 
 
X 
X 
Physical 
examinationa,g 
X 
X 
 
X 
X 
X 
X 
X 
 
 
X 
X 
Targeted postdose 
physical 
examination of 
motor effectsh 
 
X 
 
X 
X 
X 
X 
X 
 
 
 
 
Serum pregnancy 
testi 
X 
 
 
 
 
 
 
 
 
 
 
 
Urine pregnancy 
testi 
 
X 
 
X 
X 
X 
X 
X 
 
 
 
 
Adverse event 
monitoring 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 


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Timing of 
Assessment (Visit 
Window, if 
applicable) 
Event/Assessment 
Screeninga 
Treatment 
Follow-up 
ET 
Wk -4 to 
Wk -1 
Wk 1 
Wk 5 
(±3 
days) 
Wks  
(±1 
Wk) 
Wks  
(±1 
Wk) 
Wks  
(±1 
Wk) 
Wk 97  
(±1 
Wk) 
Dose 
Modification 
Assessmentsb 
Additional 
CSF 
Collectionc 
(Optional) 
Wk 101  
(±1 Wk) 
9 
13 
25 
17, 21 
29, 33 
37 
49 
41, 45 
53, 57 
61 
73 
Day -28 to 
Day -1 
Day 1 
Day 2d 
65, 69 
77, 81 
85 
89, 93 
Prior and 
concomitant 
medications 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
Blood 
pressure/pulsej 
X 
X 
 
X 
X 
X 
X 
X 
 
 
X 
X 
Temperature 
X 
X 
 
X 
X 
X 
X 
X 
 
 
X 
X 
Weighta,f 
X 
X 
 
 
 
 
X 
X 
 
 
X 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
Electrocardiogramk 
X 
 
 
 
 
 
X 
 
 
 
 
 
Pre-LP PT and 
plateletf,l 
 
X 
 
X 
X 
X 
X 
X 
 
X 
 
 
Clinical laboratory 
evaluationsa,f,m 
X 
X 
 
X 
 
X 
X 
X 
X 
 
 
 
Urine dipsticka,f,m  
X 
X 
 
 
 
X 
X 
X 
 
 
X 
X 
Blood sample for 
PKn 
 
X 
 
X 
 
 
X 
 
 
 
 
 
Blood sample for 
immunogenicity 
 
X 
 
X 
 
 
X 
 
 
 
 
 
CSF sample for 
safety, exposure, 
and PDo 
 
X 
 
X 
X 
X 
X 
X 
 
X 
 
 
Brain magnetic 
resonance imaging 
(MRI)p 
X 
 
 
 
 
 
X 
X 
 
 
 
Xq 


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Timing of 
Assessment (Visit 
Window, if 
applicable) 
Event/Assessment 
Screeninga 
Treatment 
Follow-up 
ET 
Wk -4 to 
Wk -1 
Wk 1 
Wk 5 
(±3 
days) 
Wks  
(±1 
Wk) 
Wks  
(±1 
Wk) 
Wks  
(±1 
Wk) 
Wk 97  
(±1 
Wk) 
Dose 
Modification 
Assessmentsb 
Additional 
CSF 
Collectionc 
(Optional) 
Wk 101  
(±1 Wk) 
9 
13 
25 
17, 21 
29, 33 
37 
49 
41, 45 
53, 57 
61 
73 
Day -28 to 
Day -1 
Day 1 
Day 2d 
65, 69 
77, 81 
85 
89, 93 
Study drug 
administration via 
IT injectionr 
 
X 
 
X 
X 
X 
X 
X 
 
 
 
 
Abbreviations: CSF = cerebrospinal fluid; C-SSRS = Columbia-Suicide Severity Rating Scale; ET = early termination; h = hour; ICF = informed consent form; 
IT = intrathecal; LP= lumbar puncture; PBA-s = Short Problem Behaviors Assessment; PD = pharmacodynamics; PK = pharmacokinetics; PT = prothrombin 
time; UHDRS = Unified Huntington’s Disease Rating Scale.
a If Screening is within 4 weeks of the completion of the Phase 1b/2a study, the values from the final visit in the parent study can be used for this assessment. 
b Dose modification will occur at the next scheduled visit from the date of implementation of this amendment (Amendment 1.0). In addition to the assessments 
performed at every dosing visit, the UHDRS and clinical laboratory evaluations should be performed at the visit when a dose is changed. See Section 4.1 for 
more details.  
c Collect CSF 14 days (± 3 days) after the first dose and 14 days (± 3 days) after sixth dose. Patients should be monitored after the lumbar puncture per 
institutional standards. 
d This visit will be a phone call. 
e Clinical effects measures and C-SSRS should be performed prior to any other assessments that day. 
f This assessment can be done up to 1-week predose, at each applicable dosing visit. 
g Physical examination includes (at a minimum): head, eyes, ears, nose, throat, respiratory, cardiovascular, gastrointestinal, musculoskeletal, psychiatric, and 
neurologic systems. For dosing days, physical examination should be done before the dose is given.  
h Targeted postdose physical examination to assess potential motor effects focuses on the neurologic system, with special attention to the motor system, upper 
and lower extremity measures of strength, tone, reflexes, and ambulation. This should be performed at 1 and 4 hrs postdose (± 15 mins). 
i Negative serum pregnancy test documented at Screening for female patients. Negative urine pregnancy test documented predose for female patients. 
j Blood pressure (systolic and diastolic) and pulse: measured ≤30 mins predose and 4 hours (±15 mins) postdose at each dosing visit. Patient must rest quietly for 
≥3 minutes prior to measuring.    
k Electrocardiogram should be performed (in triplicate) predose, after patient has been resting quietly for ≥5 minutes. 
l Blood sample tested locally for platelet count and prothrombin time pre-LP to confirm safe to proceed with the lumbar puncture. 
 
 


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m Parameters to be assessed are detailed in Table 3. 
n Performed predose, and 1 and 3 hours (±15 mins) postdose at noted visits. For patients on the intensive PK schedule, follow additional assessments summarized 
in Table 2.  
o CSF samples will be tested locally for safety (total protein, glucose and cell counts [white blood cell counts with differential]). No more than 10 mL of CSF 
total will be collected for safety, exposure, and PD biomarkers. 
p Only at Screening and at Weeks 49 and 97. The screening visit MRI should be completed after eligibility has been confirmed. On Weeks 49 and 97 the MRI 
must be performed within 7 days pre-dose.   
q Complete an MRI at the ET visit if the last per-study protocol MRI was obtained more than 6 months before the ET visit. 
r Patients should be active through 30 minutes postdose. 


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Table 2 
Schedule of Additional Assessments for Intensive Pharmacokinetic Patients 
Timing of Assessment  
(Visit Window, if applicable) 
Event/Assessment 
Week 1  
Week 73 
7 Days 
(±3 
days) 
Post 
Week 73 
Day 1 
Day 2 
Predose 
0-4 hr 
Postdose 
4-24 hr 
Postdose 
Predose 
30 min 
±5 min 
Postdose 
1 hr 
±15min 
Postdose 
3 hr 
±15 min 
Postdose 
24 hr 
±15 min 
Postdose 
Blood sample for PKa 
 
 
 
 
X 
X 
X 
X 
X 
X 
Urine sample for PK assessments 
 
X 
X 
 
 
 
 
 
 
 
C-SSRSb 
 
 
 
 
 
 
 
 
 
X 
AE Monitoringb 
 
 
 
X 
 
 
 
 
 
X 
Concomitant Medicationsb 
 
 
 
X 
 
 
 
 
 
X 
Abbreviations: AE = adverse event; C-SSRS = Columbia-Suicide Severity Rating Scale; hr = hour; min = minute; PD = pharmacodynamic; PK = 
pharmacokinetic. 
aFollow “blood sample for PK” timepoints in Table 1 for Week 1 blood PK.  
 
bThe visits on Day 2 and 7 days (±3 days) post-Week 73 are unique to the patients being evaluated for intensive PK and additional safety monitoring is required. 
 


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4.3 
Study Endpoints 
Safety Endpoints: 
The number of patients with AEs, severity of AEs, number of patients with SAEs, clinically 
significant changes in laboratory values, and the number of patients who withdraw due to AEs. 
Clinical Effects Endpoint(s): 
 Change from baseline in the Total Functional Capacity (TFC), administered as part of the 
Unified Huntington’s Disease Rating Scale (UHDRS) 
 Change from baseline in the motor, cognitive, independence, and functional assessments 
administered as part of the UHDRS 
 Change from baseline in the composite UHDRS (cUHDRS) 
 Change from baseline in the Short Problem Behaviors Assessment (PBA-s) 
Pharmacodynamic Endpoints: 
 Change from baseline in the concentration of mHTT protein in CSF  
 Changes from baseline MRI of the brain 
 Change from baseline in exploratory biomarkers, including but not limited to 
neurofilament light (NFL) 
PK Endpoints: 
 PK parameters of WVE-120101 in plasma  
 WVE-120101 and WVE-120101-related metabolite excretions in urine 
 Concentration of WVE-120101 in CSF  
4.4 
Safety Monitoring Committee Reviews 
A Safety Monitoring Committee (SMC) (Section 13.1) will review aggregate safety data while 
the Phase 1b/2a study is ongoing. Safety data will be reviewed periodically and on an ad hoc 
basis should any emergent safety concerns arise. Recommendations based on these reviews will 
be provided to the Sponsor. Any decisions regarding the stopping of the WVE-HDSNP1-001 
study will apply to this study if appropriate. The SMC will cease to review safety data from this 
study once the Phase 1b/2a study is complete.  


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5 PATIENT SELECTION AND WITHDRAWAL CRITERIA 
Approximately 50 patients will be enrolled. Patients will be assigned to study treatment only if 
they qualify according to all of the following inclusion and exclusion criteria. During Screening, 
patients who do not meet all remaining inclusion/exclusion criteria will be considered screen 
failures. Patients who fail screening may be rescreened once if the reason for screen failure is 
transient and the patient is expected to return to normal after recovery. 
5.1 
Inclusion Criteria 
1. Patient has documented ability to understand the written study ICFs and has provided 
signed written informed consent prior to any study procedures.  
2. Patient successfully completed their Day 168 or 196 visit (depending upon dosing cohort 
and requirements in a given country) of the Phase 1b/2a study with WVE-120101, 
WVE-HDSNP1-001. 
3. In the opinion of the Investigator, the patient is able to tolerate all study procedures, is 
willing to comply with all other protocol requirements, and tolerated study drug in the 
parent study. 
4. Patient is willing to practice highly effective contraception for the duration of the study if 
patients or their partners are of childbearing potential. Non-childbearing potential and 
highly effective methods of contraception are defined in the protocol (Section 5.2.1). 
5.2 
Exclusion Criteria 
1. Clinically significant medical finding on the physical examination other than HD that, in 
the judgment of the Investigator, will make the patient unsuitable for participation in 
and/or completion of the study procedures. 
2. Received an investigational drug other than WVE-120101, including an investigational 
oligonucleotide, within the past 1 year or 5 half-lives of the drug, whichever is longer. 
3. Implantable CNS device that may interfere with ability to administer study drug via 
lumbar puncture or undergo MRI scan. 
4. Diagnostic and Statistical Manual of Mental Disorders 5th Edition (DSM-5) diagnosis at 
the Screening Visit of active alcohol, cannabinoid, or other substance use disorder 
(except nicotine). 
5. Positive for opioids (unprescribed), cocaine, amphetamines, methadone, barbiturates, 
methamphetamine, or phencyclidine at the Screening Visit.  
6. Pregnant (as determined by a serum pregnancy test) or breast feeding at the Screening 
Visit, or plans to become pregnant during the course of the study. 


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7. Clinically significant laboratory abnormality at Screening, including, but not limited to: 
a. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) values at 
Screening or Baseline >3 times the upper limit of normal (ULN). 
b. Renal insufficiency, defined as either serum creatinine >1.8 mg/dL or creatinine 
clearance <40 mL/min. 
8. Clinically significant abnormality at Screening electrocardiogram (ECG), including but 
not limited to a confirmed QT interval corrected for heart rate (QTc) ≥450 msec for 
males or ≥470 msec for females. 
9. Clinically significant cardiovascular, endocrine, hepatic, renal, pulmonary, 
gastrointestinal, neurologic, malignant, metabolic, psychiatric, or other condition that, in 
the opinion of the Investigator, precludes the patient’s safe participation in the study or 
would interfere with the study assessments.  
10. Bone, spine, bleeding, or other disorder that exposes the patient to risk of injury or 
unsuccessful lumbar puncture. 
11. Inability to undergo brain MRI (with or without sedation).  
12. In the opinion of the Investigator, deemed to be at significant risk for suicidal behavior 
13. Involved directly or indirectly in the conduct and administration of this study as an 
Investigator, sub-investigator, study coordinator, or other study staff member, or the 
patient is a first-degree family member, significant other, or relative residing with one of 
the above persons involved directly or indirectly in the study. 
14. Anticipates using antiplatelet or anticoagulant therapy during the course of the study. 
Patients who received antiplatelet or anticoagulant therapy must complete one of the 
following washout periods before the Screening Visit:  
a. A 7-day washout period for antiplatelet therapy, 
b. A 1-day washout period for anticoagulants (except warfarin), or 
c. A 5-day washout period for warfarin. 
5.2.1 
Additional Study Restrictions 
As noted in the inclusion criteria, patients or their partners of childbearing potential must 
practice true abstinence or use highly effective methods of contraception. True abstinence is 
defined as refraining from heterosexual intercourse for the duration of the study. Non-
childbearing potential and highly effective methods of contraception are defined in Section 
5.2.1.1 and Section 5.2.1.2.  
5.2.1.1 
Non-Childbearing Potential 


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Non-childbearing potential is defined as a female who meets either of the following criteria:  
 Postmenopausal state defined as no menses for 12 months without an alternative medical 
cause, or 
 Documented hysterectomy, bilateral tubal ligation, or bilateral oophorectomy  
5.2.1.2 
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 birth control methods. Such methods are defined as 
one of the following: 
 True abstinence, defined as refraining from heterosexual intercourse for the duration of 
the study, when in line with the preferred and usual lifestyle of the subject 
 Vasectomized partner (if that vasectomized partner is the sole sexual partner and has 
received medical assessment of the surgical success of the vasectomy) 
 An intrauterine hormone-releasing system (IUS) 
 Combined (estrogen and progesterone containing) hormonal contraception associated 
with inhibition of ovulation (oral, intravaginal or transdermal combined) 
 Progesterone-only hormonal contraception associated with inhibition of ovulation (oral, 
injectable, or implantable) 
 An intrauterine device (IUD) 
Note that periodic abstinence (calendar, symptothermal, post-ovulation methods), 
withdrawal (coitus interruptus), spermicides only, and lactational amenorrhoea are not 
acceptable methods of contraception.  
5.3 
Withdrawal and Discontinuation 
Patients 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. 
Patient participation in the study may also be stopped at any time at the discretion of the 
Investigator or at the request of the Sponsor, as described in Section 5.3.1. Patients who 
withdraw or discontinue from study treatment will no longer receive investigational drug.  
5.3.1 
Withdrawal of Patient from the Study 
Patients must be withdrawn from the study for any of the following: 
 The patient withdraws consent 


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 At the discretion of the Investigator for medical reasons 
 At the discretion of the Investigator or Sponsor for noncompliance 
 Significant protocol deviation 
 Termination of the study by the Sponsor (See Section 14.4 for additional details) 
Any patient who withdraws their consent for participating in the study will be removed from 
further treatment and study observation immediately upon the date of request. These patients 
should be encouraged to complete the early termination study procedures and observations 
(Section 4.1.4) at the time of withdrawal. All information, including the reason for withdrawal 
from the study, must be recorded in the electronic case report form (eCRF) and source 
documentation. 
5.3.2 
Discontinuation of Study Treatment 
A patient may permanently discontinue study treatment for any of the following: 
 The patient is withdrawn from the study (Section 5.3) 
 The patient experiences a serious or intolerable AE that in the Investigator’s opinion 
requires treatment discontinuation 
 A change in the patient’s medical condition not consistent with the protocol requirements 
or that justifies withdrawal from the study or study drug 
 Pregnancy (refer to Section 9.5)  
If a patient discontinues treatment, they will be encouraged to remain in the study to be 
monitored and complete applicable study related procedures (see Section 4.1.4 for more details), 
unless consent is withdrawn. Patients who discontinue treatment due to an AE (Section 9) or 
pregnancy (Section 9.5) may require longer follow-up. 
The reason for discontinuation of study treatment must be recorded in the eCRF and source 
documentation. 
5.3.3 
Lost to Follow-up 
Patients who fail to return for final 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 the patient is unreachable by telephone, a 
registered letter will be sent to the patient requesting him or her to contact the study center. If 
contact with the patient is not established after all above attempts, this patient will be considered 
as lost to follow-up. 
5.3.4 
Replacements 


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Patients will not be replaced in this study. 
6 INVESTIGATIONAL DRUG  
6.1 
Method of Assigning Patients to Investigational Drug  
Patients who qualify according to all of the inclusion and exclusion criteria will be enrolled into 
the study. Patients will be assigned to dose groups according to Section 2.1. 
6.2 
Dose and Investigational Drug Administration 
6.2.1 
Identity of Investigational Drug 
6.2.1.1 
WVE-120101 
WVE-120101 will be provided as a lyophilized powder in a clear glass vial with a Teflon™ lined 
rubber stopper, aluminum overseal and plastic flip-off cap. Each vial contains 8 mg of WVE-
120101. 
WVE-120101 drug substance is the fully neutralized sodium salt of a mixed 2-O-methyl 
ribonucleic acid/deoxyribonucleic acid oligonucleotide 20-mer containing a combination of 3-O 
to 5-O linked phosphodiester and phosphorothioate linkages, the latter of which consist of a 
prescribed combination of stereodefined Rp and Sp linkages.  
International Nonproprietary Name (INN): To be assigned 
6.2.2 
Administration of Investigational Drug  
Investigational drug (WVE-120101) will be administered every 4 weeks for up to 97 weeks. The 
route of administration will be IT by direct lumbar injection, and the total volume of the injection 
will be 10 mL. WVE-120101 should be reconstituted and diluted with 0.9% sodium chloride 
prior to injection in accordance with instructions in the pharmacy manual. 
The lumbar puncture will be performed by an appropriately trained individual. Up to 1 week 
prior to the lumbar puncture, a blood sample will be tested locally for platelet count and 
prothrombin time (PT) to confirm that it is safe to proceed with the lumbar puncture 
(Section 8.1.7). Patients should not be sedated during administration of study drug. The Study 
Operations Manual provides detailed instructions on the procedure to be used for lumbar 
puncture. 
Within ≤15 minutes prior to administration of study drug, CSF samples will be collected for 
safety assessments (Section 8.1.8), drug concentrations (Section 8.2), and PD (Section 8.3) 
assessments, per the Schedule of Assessments (Table 1). No more than 10 mL of CSF should be 
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Immediately after each administration of study drug, all patients should be ambulatory for 
approximately 30 minutes. Formal physical examinations targeting the neurological system will 
be performed at the time points noted in the Schedule of Assessments (Section 4.2). 
6.3 
Treatment Compliance 
Provided that a patient attends the clinic visits, treatment noncompliance is not expected to be an 
issue. Thus, every attempt will be made to ensure regular visits by the patient to the clinic per the 
study schedule. Investigative staff will make every effort to contact patients who miss visits in 
order to obtain as much follow-up information as possible. 
6.4 
Management of Clinical Supplies 
6.4.1 
Investigational Drug Packaging and Storage 
WVE-120101 will be supplied by the Sponsor as a lyophilized powder in clear glass vials.  
All study drugs will be transported, received, stored, and handled in accordance with the 
container or product label, the instructions supplied to the pharmacy, relevant institution’s 
Standard Operating Procedures (SOPs), and applicable regulations. Appropriate storage and 
transportation conditions will be maintained for the study drug from the point of manufacture up 
to delivery of the study drug.  
Study drugs will be stored at 2ºC to 8ºC in a locked area accessible only to the pharmacy 
personnel until reconstitution. WVE-120101 reconstituted and diluted solution for injection 
contains no preservatives and should be administered without delay or within 4 hours of 
reconstitution.  
Partially used, unused, or damaged vials should be disposed of according to Sponsor instructions. 
Details on reconstitution and administration are provided in the Pharmacy Manual and IB.  
6.4.2 
Investigational Drug Accountability 
The Investigator will maintain accurate records of receipt of drug supplies, including dates of 
receipt. In addition, accurate records will be kept regarding when each treatment is administered, 
which patients received treatment, and the name of the personnel administering the treatment. 
Reasons for departure from the expected treatment regimen will also be recorded. Only trained 
site staff are permitted to treat study patients. A study monitor will review the accountability 
records onsite.  
6.4.3 
Other Supplies 
The study sites will be provided with the IB, Study Operations Manual, Pharmacy Manual, 
Imaging Manual, Laboratory Manual, laboratory kits, and other materials, as appropriate. 
6.4.3.1 
Diluent 


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The diluent is 0.9% Sodium Chloride Injection sterile, preservative-free solution. It will be 
provided in commercially available single-use vials or plastic ampoules.  
7 BLINDING AND RANDOMIZATION 
This is an open-label study. If the DEC and SMC endorse multiple dosing at a dose higher than 
16 mg in the Phase 1b/2a study, patients in this OLE study may be randomized to new dose 
levels pending Sponsor decision. The randomization scheme will be assigned by an interactive 
voice/web response system (IXRS), which will send notifications of the treatment assignment to 
the designated pharmacy personnel.  
8 METHODS OF ASSESSMENT AND ENDPOINTS 
8.1 
Safety Assessments 
 Adverse events (Section 9) 
 Medical history and demographics 
 Concomitant medications 
 Physical examinations (including neurological and psychiatric) 
 Vital signs 
 Height and weight 
 Electrocardiograms 
 Clinical laboratory evaluations (including clinical chemistry, hematology, and urinalysis) 
 Magnetic resonance imaging (Section 8.5) 
 Cerebrospinal fluid sample evaluations (cell count and total protein) 
 Suicidality assessment 
 Pregnancy testing 
Any abnormal laboratory test results (hematology, clinical chemistry, or urine) or other safety 
assessments (e.g., vital sign measurements, C-SSRS) that are believed to be clinically significant 
in the medical and scientific judgment of the Investigator are to be recorded as AEs or SAEs. 
8.1.1 
Medical History and Demographics  
Any changes in medical history since the completion of the parent study (WVE-HDSNP1-001) 
will be obtained at the Screening visit. Investigator assessment of medical history at Screening 


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will include information regarding any significant medical, surgical, psychiatric, and/or 
neurological conditions and treatments.  
The current stage of HD, treatments received, and other details about this condition will be 
recorded.  
Demographic data will include date of birth, sex, ethnic categorization, and race. 
8.1.2 
Prior and Concomitant Medications 
Any treatments/medications taken for HD during the time between the end of the Phase 1b/2a 
study and the patient signing the ICF for the OLE study will be recorded in the patient’s eCRF.  
All concomitant medications used from the time the patient signs the OLE ICF to the end of the 
patient’s participation in the OLE study will be recorded in the patient’s eCRF.  
The minimum requirement is that the drug name, dose, indication, and the dates of 
administration are 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 patient’s eCRF. 
Any concomitant medication deemed necessary for the welfare of the patient during the study 
may be given at the discretion of the Investigator. However, it is the responsibility of the 
Investigator to ensure that details regarding such medication are recorded in full in the eCRF.  
8.1.2.1 
Restricted Concomitant Medications 
Use of all antiplatelet (e.g., aspirin, prasugrel, etc.) or anticoagulant (e.g., heparin, warfarin, etc.) 
therapy is restricted throughout the study. Patients who take antiplatelet therapy will need to 
complete a 7-day washout period before undergoing intrathecal administration of the study drug. 
Patients who receive most anticoagulant therapies will need to complete a 1-day washout period 
before undergoing intrathecal administration of the study drug. However, because of the longer 
plasma half-life, patients taking warfarin will need to complete a 5-day washout period before 
undergoing intrathecal administration of the study drug.  
8.1.3 
Physical Examination 
A physical examination will be performed at the time points noted in the Schedule of 
Assessments (Section 4.2).  
Immediately postdose (through 4 hours postdose), a targeted physical exam to assess potential 
motor effects will be performed. This exam will include a neurologic examination with special 
attention to the motor system, and upper and lower extremity measures of strength, tone, 
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At all other time points, the physical exam must include (at a minimum) head, eyes, ears, nose, 
throat, respiratory, cardiovascular, gastrointestinal, musculoskeletal, psychiatric, and neurologic 
systems. Other systems should be evaluated as appropriate.  
Physical findings will be recorded in the eCRF and source documents.  
8.1.4 
Vital Signs 
Blood pressure (systolic and diastolic), temperature, and pulse will be measured by medically 
qualified personnel at the time points described in the Schedule of Assessments (Section 4.2) and 
recorded in the eCRF and source documents. Vital signs measurements will be taken as per 
standard site practice, after the patient has been resting quietly (either lying flat or sitting, 
whichever is most appropriate for the condition of the patient) for a period of at least 3 minutes. 
As feasible, the same position (either sitting or lying) should be used for all subsequent vital 
signs measurements during the study for an individual patient. If the initial reading is high, the 
measurements will be repeated twice and the average of the 3 readings will be used. 
8.1.5 
Height and Weight 
The patient’s height and weight will be measured at the time points described in the Schedule of 
Assessments (Section 4.2) and recorded in the eCRF and source documents. 
8.1.6 
12-Lead ECG 
Computerized, good quality, 12-lead ECGs will be recorded in triplicate at the time points 
described in the Schedule of Assessments (Section 4.2). Recordings will be obtained in the 
supine position after the patient has rested comfortably for ≥5 minutes.  
The ECG tracing will be submitted and read by a centralized reviewer (details will be provided 
in the ERT® Study Manual). The following should be recorded on the trace and eCRF: whether 
the ECG is normal or abnormal and, if deemed abnormal, whether the abnormality is clinically 
significant or not clinically significant, with the abnormality noted.  
8.1.7 
Clinical Laboratory Evaluations 
Clinical laboratory safety testing will be collected at the time points described in the Schedule of 
Assessments (Section 4.2) and recorded in the eCRF and source documents. A blood sample will 
be tested locally up to 1 week prior to the lumbar puncture to determine platelet count and 
prothrombin time, and thereby confirm that it is safe to proceed with the lumbar puncture. Other 
safety laboratory samples will be analyzed at a central laboratory. Local testing on these samples 
may be conducted as clinically indicated.  
The parameters to be assessed are presented in Table 3.  


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Table 3 
Clinical Laboratory Parameters 
Hematology 
Coagulation 
Clinical chemistry 
Urine dipstick 
Complete blood count, including: 
• 
White blood cell count (with 
differential) 
• 
Red blood cell count  
• 
Hemoglobin 
• 
Hematocrit 
• 
Platelet count 
• 
Reticulocyte count 
• 
Mean corpuscular volume 
• 
Mean corpuscular hemoglobin 
• 
Mean corpuscular hemoglobin 
concentration 
Measures of Inflammation, 
including: 
• 
High Sensitivity C-reactive 
protein  
• 
Complement  
Activated partial 
thromboplastin time  
Prothrombin time  
Fibrinogen 
 
Sodium 
Potassium  
Chloride 
Bicarbonate 
Blood urea nitrogen  
Creatinine 
Creatine 
phosphokinase 
Alanine 
aminotransferase 
Aspartate 
aminotransferase 
Alkaline phosphatase 
Bilirubin 
Urinalysis  
 
8.1.8 
Cerebrospinal Fluid Safety Lab 
A CSF safety laboratory sample obtained at the times noted on the Schedule of Assessments 
(Section 4.2) will be evaluated at a local lab. The following parameters will be assessed: total 
protein, glucose, and cell counts (white blood cell counts with differential).  
8.1.9 
Suicidality Assessment (Columbia-Suicide Severity Rating Scale) 
The C-SSRS is a measure of suicidal ideations and suicidal behaviors20. The C-SSRS is 
provided in Appendix 1. The ‘since last visit’ form, will be performed at all time points noted in 
the Schedule of Assessments (Section 4.2). A trained rater will complete this scale. The findings 
should be confirmed by the clinical opinion of the Investigator. 
The Investigator should be notified if a patient responds “yes” to any of the questions. The 
Investigator will provide care according to local standards, which may include referral to 
specialists, medical treatment, or hospitalization as necessary. 
8.1.10 
Pregnancy Testing  
For female patients of childbearing potential, a negative serum pregnancy test must be 
documented at the Screening Visit and a negative urine pregnancy test must be documented at 
the times noted on the Schedule of Assessments (Section 4.2). The serum pregnancy test will be 
determined by a central lab; urine pregnancy tests will be performed locally.  
8.1.11 
Drug Screening 


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A urine drug screen for opioids, cocaine, amphetamines, methadone, barbiturates, 
methamphetamine, and phencyclidine will be performed at the times noted on the Schedule of 
Assessments (Section 4.2). Drug screen tests will be evaluated by a central laboratory. 
8.2 
Pharmacokinetic Assessments  
Samples for analysis of PK of WVE-120101 and WVE-120101-related metabolite excretions in 
plasma and urine and concentrations of WVE-120101 in CSF will be collected at the time points 
specified on the Schedule of Assessments (Section 4.2). The date and time of the sample 
collection will be recorded.  
Patients who are entering the study may be requested to consent to two additional lumbar 
punctures (LP) to provide CSF samples at two weeks after the first dose, and two weeks after the 
sixth dose to allow for more robust PK/PD modeling (see Table 1 for more details). These 
additional CSF samples will be optional, and consent will be collected as a stand-alone question 
in the Informed Consent Form. If a patient has already passed the first dose, but not the sixth, 
and is willing to undergo the additional LP, then CSF will be collected 2 weeks after the sixth 
dose.  
In addition to the above two CSF samples, patients at certain participating sites will undergo 
additional intensive PK blood and urine sampling as noted in Table 2. This sampling will include 
additional time points for plasma and a 24-hour urine collection.  
Samples will be analyzed by a central laboratory to determine concentrations of WVE-120101 
using a validated method.  
8.3 
Pharmacodynamic Assessments 
A CSF sample will be collected at the time points noted in the Schedule of Assessments 
(Section 4.2) to determine the change from baseline in concentration of mHTT protein. In 
addition, NFL and other exploratory biomarkers in CSF, plasma, and serum may be assessed.  
The study may utilize the method described in Wild et al.21 or an alternative method to 
determine levels of mHTT protein.  
8.4 
Immunogenicity Assessments 
Serum samples will be collected at the times noted on the Schedule of Assessments (Section 4.2) 
and analyzed at a central laboratory for measurement of anti-drug antibodies to WVE-120101.  
8.5 
Magnetic Resonance Imaging 
A 3 Tesla (3T) MRI of the whole brain (without contrast) will be performed at the time points 
noted on the Schedule of Assessments (Section 4.2). Sedation is permitted during the MRI. All 
other eligibility should be confirmed prior to the MRI scheduled at the Screening visit.  


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The MRI will be assessed for safety purposes, in addition to exploratory structural assessments.  
Exploratory assessments will include, but are not limited to, volumetric assessments. Changes in 
MRI of the brain will be characterized in patients receiving WVE-120101. 
The MRI will be performed by an appropriately trained individual. Detailed instructions on how 
the MRI will be performed and transferred to the central reader are provided in the Imaging 
Manual. The scans will be evaluated by a central reader. 
8.6 
Assessment of Clinical Effects 
8.6.1 
Unified Huntington’s Disease Rating Scale  
The Unified Huntington’s Disease Rating Scale (UHDRS) is a research tool developed by the 
Huntington Study Group to provide a uniform assessment of the clinical features and course of 
HD22. The scale consists of 6 subtests, including motor assessment, cognitive assessment, 
behavioral assessment, an independence scale, functional assessment, and TFC, and is provided 
in Appendix 2. In addition, analyses will be performed using the composite UHDRS (cUHDRS), 
which is based on 4 of the UHDRS components, namely the TFC, Symbol Digit Modalities Test 
(SDMT), Stroop Interference test, and the total motor impairment score23. All subtests of the 
UHDRS should be performed except the behavioral assessment, as the PBA-s (Section 8.6.2) 
collects similar behavioral information.  
The motor assessment evaluates motor features of HD with standardized ratings of oculomotor 
function, dysarthria, chorea, dystonia, gait, and postural stability. The total motor impairment 
score is the sum of all the individual motor ratings, with higher scores indicating more severe 
motor impairment than lower scores. 
The cognitive assessment consists of a lexical verbal fluency test, SDMT, and the Stroop 
Interference test. The Stroop Test results are reported as the raw number of correct answers given 
in a 45-second period. Results for the other tests are reported as the raw number of correct 
responses. Higher scores indicate better cognitive performance. 
The independence scale is used to follow disease progression in functional disability. The scale 
is rated from 100 (no special care needed) to 0 (tube-fed, total bed care).  
The functional assessment checklist is a 25-question assessment that screens for capacity to 
complete the tasks mentioned in the assessment. The questions are asked in the presence of a 
family or friend to get the clinician’s best judgment based on both responses. A response of 
“yes” is given a score of 1. A higher score indicates better functioning.  
The TFC is a brief interview involving the patient and a close family member or friend familiar 
with the patient’s functioning. The measure has 5 items and addresses basic activities of living: 
occupation, handling finances, domestic responsibilities, activities of daily living (e.g., eating, 
dressing, bathing), and level of care.  


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8.6.2 
Short Problem Behaviors Assessment 
The PBA-s is a shorter version of the Problem Behaviors Assessment for HD (PBA-HD), a semi-
structured interview designed to elicit information about behavioral symptoms relevant to HD. 
The shorter version was developed by the Behavioral Phenotype Working Group of the 
European Huntington’s Disease Network (EHDN)24, and is contained in Appendix 3. 
The PBA-s contains 11 items, each measuring a different behavioral problem that is rated for 
both severity and frequency on a 5-point scale. Severity and frequency ratings are multiplied to 
provide an overall score for each symptom.  
Interviews are conducted with the patient. The final rating is determined by assessing all 
available information, including the interviewer’s own observations of the patient’s behavior. A 
caregiver should not be interviewed as part of the PBA-s for this study.  
9 ADVERSE EVENTS 
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. 
Adverse event information will be collected beginning at enrollment (date of signed informed 
consent) and up to the end of the study. All ongoing AEs at the end of the study will be followed 
to resolution, or until the Investigator and the Sponsor agree that further follow-up is not 
required. 
An AE is defined as any untoward medical occurrence in a patient enrolled into this study 
regardless of its causal relationship to study treatment. Patients will be instructed to contact the 
Investigator at any time after Screening if any symptoms develop. 
A TEAE is defined as any event not present before exposure to study treatment or any event 
already present that worsens in either severity or frequency after exposure to study treatment.  
9.1 
Eliciting and Documenting Adverse Events 
All AEs reported or observed during the study, including AEs resulting from concurrent 
illnesses, reactions to concurrent medications, or progression of disease states, 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 event 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. 
All AEs will be followed to adequate resolution. The sites will be provided with completion 
guidelines for the eCRF, which will further guide them on how to record the data, including AEs.  
Any medical condition that is present at the time the patient is screened but does not worsen 
should not be reported as an AE. However, if it worsens at any time during the study, it should 


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be recorded as an AE. This includes any spontaneously reported worsening of depression, 
i.e., not based on the study rating scales. 
In addition to observations of the patient, 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. Worsening of symptoms that are only detected on clinical effects rating scales will not be 
reported as AEs.  
Adverse events will be assessed at each visit by direct questioning as well as elicited from 
physical examination by site staff. In addition, all sites in the study must ensure patients 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.  
9.2 
Definitions of Adverse Event Severity and Relationship to Study Drug 
9.2.1 
Severity 
The severity, or intensity, of an AE refers to the extent to which an AE affects the patient’s daily 
activities. Adverse event severity will be evaluated using the criteria described in Table 4.  
Table 4 
Definitions of AE Severity 
AE Severity 
Definition  
Mild 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated. 
Moderate 
Moderate; minimal, local or noninvasive intervention indicated. 
Severe 
Severe or medically significant but not immediately life-threatening; hospitalization or 
prolongation of hospitalization indicated; disabling; limiting self-care. 
Abbreviations: AE = adverse event. 
Changes in the severity of an AE should be documented in the eCRF to allow an assessment to 
be performed of the duration of the event at each level of severity.  
9.2.2 
Relationship to Study Drug 
The Investigator’s assessment of an AE’s relationship to study treatment is part of the 
documentation process, but it is not a factor in determining what is or is not reported in the study. 
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 9.3.4).  
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 5. 


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Table 5 
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 produced by other 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. 
Abbreviation: AE = adverse event. 
9.3 
Serious Adverse Events  
9.3.1 
Serious Adverse Event Criteria 
An SAE is defined as any event that results in death, is immediately life threatening, requires 
inpatient hospitalization or prolongation of existing hospitalization, results in persistent or 
significant disability/incapacity, or is a congenital anomaly/birth defect not present at 
Prescreening. Important medical events that may not result in death, be life threatening, or 
require hospitalization may be considered SAEs when, based upon appropriate medical 
judgment, they may jeopardize the patient 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. A life-threatening event does not include an AE that, had it 
occurred in a more severe form, might have caused death.  
Serious AEs must be reported (Section 9.3.4) and will be followed through the follow-up visit. 
Serious AEs that occur after the final follow-up visit need not be reported unless the Investigator 
considers them related to study drug.  
The Sponsor clinical physician will provide a Sponsor causality statement for all SAEs.  


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9.3.2 
Suspected, Unexpected, Serious Adverse Reaction 
A suspected, unexpected, serious adverse reaction (SUSAR) is an SAE for which there is a 
reasonable possibility that the drug caused the event, and this SAE has not been previously 
identified as an expected/listed adverse event. 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 adverse events, but if it did occur, would not be considered “unexpected” for SUSAR 
reporting. As an example, a flare-up of neurological symptoms consistent with the underlying 
disease under treatment that required hospitalization would constitute an SAE; however, the 
event would not be considered unexpected. An exception would be if the reporter believed that 
investigational drug worsened the underlying neurological condition.  
9.3.3 
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 patient’s response to these measures should 
be recorded. All SAEs regardless of relationship to study drug will be followed by the 
Investigator until resolution. Clinical, laboratory, and diagnostic measures should be employed 
by the Investigator as needed to adequately determine the etiology of the event. 
9.3.4 
Serious Adverse Event Reporting 
9.3.4.1 
Reporting Requirements 
Any AE that meets SAE criteria (Section 9.3.1) 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 patient signs the ICF until completion of the 
final follow-up visit. All SAEs must also be recorded in the patient’s source documentation and 
on the AE page of the patient’s eCRF. 
The initial report should include at least the following information: 
 Study Number 
 Patient’s identification number 
 Description of the event 
 Date and time of onset of the event 
 Seriousness criteria 
 Causality assessment to study drug 


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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 and/or designee in a timely manner 
according to the procedures 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 Institutional Review Board 
(IRB) or Ethics Committee (EC). The Sponsor will be responsible for reporting to the regulatory 
authorities and Central Ethics Committees, as per local requirements. 
9.3.4.2 
SAE Contact Information 
Serious adverse event contact information is provided below: 
 
 
 
 
 
 
 
 
9.4 
Overdose 
Study drug is to be administered by trained study staff. Administration will be performed in 
accordance with the IB and instructions in the Pharmacy Manual. Any incidence of overdose 
should be recorded as an SAE.  
No clinical data are available regarding overdose with WVE-120101. As with any agent, if 
overdose occurs, general supportive measures and close observation should be instituted. Misuse 
of the study drug for illegal purposes is not expected in this study as patients have no direct 
access to the study drug. 
9.5 
Pregnancies 
If a patient or the partner of a patient becomes pregnant during the course of the study, the 
pregnancy must be reported and monitoring of the mother and fetus should be conducted until 
the pregnancy outcome.  


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If a female patient becomes pregnant during the study, she must be discontinued from study 
drug; although the patient may continue to be followed in the study. The Medical Monitor should 
be notified by the Investigator and a Pregnancy Notification Form should be completed.  
Any pregnancy (the patient or partner of a patient) should be followed until the outcome of the 
pregnancy is known. 
Although pregnancy itself is not an SAE, serious complications of the pregnancy should be 
reported to the sponsor within 24 hours of knowledge by the Investigator (e.g., if the mother is 
hospitalized for dehydration) and an SAE form must be completed. 
Based on the expected date of delivery, the Sponsor will attempt follow-up to determine the 
outcome of the pregnancy. 
10 STATISTICAL CONSIDERATIONS  
10.1 Sample Size Determination 
No sample size calculations were performed. As this is an OLE, the maximum sample size is 
fixed by the number of patients completing the WVE-HDSNP1-001 study. 
10.2 Disposition of Patients 
Screened patients are defined as any patient who signed informed consent. 
Enrolled patients consist of all screened patients who meet all eligibility criteria. 
10.3 Analysis Populations 
The safety population will include all enrolled patients who have received at least one dose of 
study medication in the OLE. The safety population will be the analysis set used for summaries 
of safety and clinical effects.  
The per-protocol population will be a subset of the safety population and include patients with no 
major protocol deviations that will interfere with the assessment of the clinical effects’ endpoints 
and with at least 80% compliance to the dosing regimen. 
The PK population will consist of all patients in the safety population with at least one post-dose 
plasma or CSF concentration measurement.  
10.4 Statistical Methods 
Analysis will include summaries of data collected in this OLE study as well as integrated OLE 
data and repeat dosing data collected in WVE-HDSNP1-001.  
10.4.1 
Study Drug Exposure and Compliance 


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The extent of study drug exposure and compliance will be summarized by dose group for the 
safety population.  
10.4.2 
Analysis of Safety Data 
The summary of safety results will be presented by dose group. All safety analyses will be 
performed on the safety population using the following common rules: 
 The OLE baseline value is defined generally as the last available value from WVE-
HDSNP1-001 before first dose in WVE-HDSNP1-002. 
 The repeat dosing baseline value is defined generally as the last available value before 
initiation of repeat dosing. Initiation of repeat dosing can occur in either WVE-
HDSNP1-001 or WVE-HDSNP1-002. 
 Adverse event observation periods are defined as follows: 
o Pre-OLE treatment AEs are AEs that developed or worsened between the date of 
signed informed consent for the OLE and the date of first dose of study drug in 
the OLE. 
o OLE on-treatment adverse events are AEs that developed or worsened from the 
first dose of study drug in the OLE to study completion/discontinuation. 
Summaries of TEAEs will include all OLE on-treatment AEs.  
o Repeat dosing on-treatment adverse events are AEs that developed or worsened 
from the first dose of repeat dosing to study completion/discontinuation. 
Initiation of repeat dosing can occur in either WVE-HDSNP1-001 or 
WVE‑HDSNP1-002. Summaries of repeat dosing TEAEs will include all repeat 
dosing on-treatment AEs.  
 For quantitative safety parameters based on central laboratory/reading measurement 
descriptive statistics will be used to summarize results and change from baseline values 
by visit and dose group. 
Adverse Events 
Treatment-emergent AEs, treatment-emergent SAEs, and TEAEs leading to treatment 
discontinuation will be summarized by dose group based on Medical Dictionary for Regulatory 
Activities (MedDRA) coding of verbatim terms reported by investigators. 
Adverse event incidence tables will present, by system organ class (SOC) and preferred term, the 
number and percentage of patients experiencing an AE. Multiple occurrences of the same event 
will be counted once in the tables. The denominator for computation of percentages is the safety 
population within each dose group. 


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Adverse event incidence tables will present, by SOC and preferred term, the number and 
percentage of patients experiencing an AE by severity and by relationship to treatment. In 
tabulating the severity of adverse events, the highest severity will be assigned to a subject with 
more than one occurrence of the same adverse event. The highest level of association will be 
reported in subjects with differing relationships for the same adverse event. 
Similar tables will be generated summarizing repeat dosing TEAEs. Listings of all AEs, SAEs, 
deaths, and AEs leading to study discontinuation will be provided.  
Clinical Laboratory Evaluations 
Summary statistics of laboratory variables including CSF safety laboratory variables will be 
calculated for each visit or study assessment by dose group. Laboratory data will also be 
categorized as low, normal, or high based on the reference ranges of the central laboratory. 
Frequencies and percentages will be presented by dose group for the shifts in these categories 
from baseline to post-baseline assessment time points. A listing of clinically significant 
hematology and chemistry findings will be provided.  
Other Safety Evaluations 
Summary statistics of vital signs, ECG, and height and weight variables will be calculated for 
each visit or study assessment by dose group.  
Columbia-Suicide Severity Rating Scale 
Listings of patients who respond “yes” to item 4 or 5 on the C-SSRS at any point in the study 
will be provided.  
Immunogenicity 
Anti-drug antibody assay results to WVE-120101 will be described categorically. Summary 
statistics for anti-drug antibody titer results will be provided.  
10.4.3 
Pharmacokinetic Analyses 
The plasma, urine, and CSF WVE-120101 concentration as well as WVE-120101-related 
metabolite data will be summarized for patients in the PK population.  
The individual patient plasma and urine concentration-time data will be listed and displayed 
graphically on linear and log scales. The plasma and urine concentration-time data will be 
summarized descriptively in tabular and graphical formats (linear and log scales).  
For each dose group, the plasma and urine WVE-120101 concentration data will be analyzed by 
noncompartmental PK analysis. The parameters listed in Table 6 will be determined. Additional 
PK parameters may be evaluated if deemed appropriate. Pharmacokinetic parameters for each 
dose group will be summarized for each WVE-120101 dose level. 
The CSF concentration data will be summarized in tabular format. 


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Table 6 
Pharmacokinetic Parameters of WVE-120101 after Multiple Dose 
Administration  
Parameter 
Definition 
Cmax  
Maximum observed concentration  
tmax  
Time of occurrence of Cmax  
AUC0-τ  
Area under the plasma concentration-time curve over the dosing interval  
AUClast  
Area under the plasma concentration-time curve from time 0 to the last measurable 
concentration.  
10.4.4 
Clinical Effects and Pharmacodynamic Analyses  
The change from baseline for clinical effects and PD endpoints will be summarized using a 
mixed model for repeated measures (MMRM) with the safety population. The MMRM will 
include the relevant baseline measure, time, dose-group and time by dose-group interactions. The 
MMRM will be used to construct 95% confidence intervals and to test if the change is 
statistically significant. Summaries will be based on data collected during the OLE and, 
separately, OLE data integrated with repeat dosing data from WVE-HDSNP1-001.  
11 REGULATORY, ETHICAL, AND LEGAL OBLIGATIONS 
11.1 Declaration of Helsinki 
The Sponsor and Investigator(s) will ensure that this study is conducted in accordance with the 
most recent revision of the Declaration of Helsinki. 
11.2 Good Clinical Practice 
The Study will be conducted according to the study protocol and SOPs that meet the guidelines 
provided by the International Conference on Harmonisation (ICH) for Good Clinical Practice 
(GCP) in clinical studies, and any other applicable local regulatory requirements. 
11.3 Institutional Review Boards/Ethics Committees 
Federal regulations and ICH guidelines require that approval be obtained from an IRB or EC 
before participation of human patients in research studies. Before study onset, the protocol, 
informed consent form, advertisements to be used for the recruitment of study patients, and any 
other written information regarding this study to be provided to the patient or the patient’s legal 
guardian must be approved by the IRB or EC. Documentation of all IRB/EC approvals and of the 
IRB/EC compliance with ICH guideline E6(R2): GCP will be maintained by the site and will be 
available for review by the Sponsor or its designee. 
All IRB/EC approvals should be signed by the chairman or designee and must identify the 
IRB/EC name and address, the clinical protocol by title or protocol number or both, and the date 
approval or a favorable opinion was granted. The study protocol, appendices, and ICFs must be 
approved by the IRB/EC.  


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The Investigator is responsible for providing written summaries of the progress and status of the 
study at intervals not exceeding one year or otherwise specified by the IRB/EC. The Investigator 
must promptly supply the Sponsor or its designee, the IRB/EC, and, where applicable, the 
institution, with written reports on any changes significantly affecting the conduct of the study or 
increasing the risk to patients. 
11.4 Informed Consent Forms 
Signed ICFs in compliance with the Declaration of Helsinki, current ICH and GCP guidelines, 
US Title 21 Code of Federal Regulations (CFR) Part 50, and applicable local regulations will be 
obtained from each patient before enrolling the patient in the study or performing any unusual or 
non-routine procedure that involves risk to the patient. Due to the natural progression of the 
disease, patients may lose the ability to understand the ICF after providing original consent. As a 
result, patients should identify a potential legally authorized representative at Screening.  
Informed consent form templates will be provided by the Sponsor 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, 
all actively participating patients or their legally authorized representatives must sign the revised 
form. 
Before Screening, each prospective patient will be given a full explanation of the study and be 
allowed to read the approved ICF. Once the Investigator is assured that the patient understands 
the implications of participating in the study, the patient will be asked to give consent to 
participate in the study by signing the appropriate ICF.  
In addition to signing the approved ICF, patients will be asked to sign a supplementary consent 
form to specify whether or not they agree to allow their leftover samples to be stored and used 
for future medical or pharmaceutical research regarding Huntington’s disease. 
The Investigator will retain the signed original ICF(s) and give a copy of the signed original 
form(s) to the patient and/or their legally authorized representative.  
11.5 Specimen Management and Storage 
Samples will only be used by the Sponsor and/or a contracted vendor for research related to the 
development of treatments for HD and stored for a maximum of 15 years.  All biological 
material will be stored and secured in a way that ensures that unauthorized access is prohibited 
and the samples are not lost, deteriorated, or destroyed accidentally or illegally.  Detailed 
instructions for sample collection, storage, processing, and shipping will be provided in the 
study-specific manual.   


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12 INVESTIGATOR’S OBLIGATIONS 
The following administrative items are meant to guide the Investigator in the conduct of the 
study in accordance with GCP guidances. These items may be subject to change based on 
industry and government SOPs, working practice documents, or guidelines. Changes will be 
reported to the IRB/EC but will not result in protocol amendments. 
12.1 Confidentiality 
All laboratory specimens, evaluation forms, reports, and other records will be identified in a 
manner designed to maintain patient confidentiality. All records will be kept in a secure storage 
area with limited access. Clinical information will not be released without the written permission 
of the patient, except as necessary for monitoring and auditing by the Sponsor, its designee, 
applicable regulatory agencies, or the IRB/EC. 
The Investigator and all employees and coworkers involved with this study may not disclose or 
use for any purpose other than performance of the study any data, record, or other unpublished 
confidential information disclosed to those individuals for the purpose of the study. Prior written 
agreement from the Sponsor or its designee must be obtained for the disclosure of any said 
confidential information to other parties. 
12.2 Investigator Documentation 
Prior to beginning the study, the Investigator will be asked to comply with ICH E6(R2) 8.2 and 
Title 21 of the United States Code of Federal Regulation by providing the following essential 
documents, including but not limited to: 
 IRB/EC approval 
 A fully executed Clinical Study Agreement 
 Curriculum vitae for the Investigator and each sub-investigator listed on the IRB/EC 
application 
 Financial disclosure information, as applicable 
 IRB/EC-approved informed consent, samples of site advertisements for recruitment for 
this study, and any other written information regarding this study that is to be provided to 
the patient 
 Laboratory certifications and normal ranges for any local laboratories used by the site 
12.3 Study Conduct 
The Investigator agrees that the study will be conducted according to the principles of 
ICH E6(R2). The Investigator will conduct all aspects of this study in accordance with all 
national, state, and local laws or regulations. Study information from this protocol will be posted 


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on publicly available clinical study registers in accordance with all national, state, and local laws 
or regulations. 
A record of patient screen failures will be maintained for patients who do not qualify for 
enrollment, including the reason for the failure. 
12.4 Adherence to Protocol 
The Investigator agrees to conduct the study as outlined in this protocol in accordance with ICH 
E6(R2) and all applicable guidelines and regulations. 
12.5 Adverse Events and Study Report Requirements 
By participating in this study, the Investigator agrees to submit reports of SAEs according to the 
timeline and method outlined in the protocol. In addition, the Investigator agrees to submit 
annual reports to the IRB/EC as appropriate. 
12.6 Investigator’s Final Report 
Where applicable, the Investigator should inform their institution of study completion; the 
investigator/institution should provide the IRB/EC with a summary of the study’s outcome and 
the Sponsor and regulatory authority(ies) with any reports required. 
12.7 Records Retention 
The Investigator/institution will retain essential documents until at least 2 years after the last 
approval of a marketing application in an ICH region and until there are no pending or 
contemplated marketing applications in an ICH region or at least 2 years have elapsed since the 
formal discontinuation of clinical development of the study drug. However, these documents will 
be retained for a longer period if required by the applicable regulatory requirements or by an 
agreement with the Sponsor. It is the responsibility of the Sponsor to inform the investigator/ 
institution as to when these documents no longer need to be retained. 
12.8 Publications 
All information regarding WVE-120101 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 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-120101 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. A Publications Committee will be 
formed (Section 13.3) to oversee any publication or presentation of the study results. 


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Subsequently, individual Investigators may publish results from the study in compliance with 
their agreements with the Sponsor. A pre-publication manuscript is to be provided to the Sponsor 
at least 45 days prior to the submission of the manuscript to a publisher. 
13 STUDY COMMITTEES  
13.1 Safety Monitoring Committee 
An unblinded, independent SMC consisting of at least 3 members (including a statistician and 2 
physicians of whom 1 must be a neurologist) will review aggregate safety data periodically and 
on an ad hoc basis should any emergent safety concerns arise. Safety data will be reviewed in 
aggregate while the WVE-HDSNP1-001 study is ongoing. The SMC will cease to review data 
from this study once the WVE-HDSNP1-001 study is complete.   
Further details regarding the SMC, including committee membership, will be provided in a SMC 
Charter.   
13.2 Clinical Advisory Committee 
A Clinical Advisory Committee, consisting of a Study Investigator and experts in Huntington’s 
disease, will be formed to provide advice regarding protocol and study conduct. Further details 
regarding the Clinical Advisory Committee, including committee membership, will be provided 
in a Clinical Advisory Committee Charter.  
13.3 Publications Committee 
A Publications Committee, consisting of Investigators participating in the study, at least one 
member of the Clinical Advisory Committee, and representatives from the Sponsor as 
appropriate, will be formed to oversee any publication or presentation of the study results, which 
will reflect the experience of all participating study centers.  
14 STUDY MANAGEMENT 
14.1 Monitoring 
14.1.1 
Monitoring of the Study 
Monitoring and auditing procedures developed by the Sponsor or designee will be followed in 
order to comply with ICH GCP guidelines.  
During the study, a monitor from the Sponsor or designee will have regular contact with the 
study center for the following: 
 Provide information and support to the Investigator(s) 
 Confirm that facilities remain acceptable 


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 Confirm that the investigational team is adhering to the protocol, that data are being 
recorded accurately in the source documents and eCRFs, and that investigational product 
accountability checks are being performed 
 Perform source data verification. This includes a comparison of the data in the eCRFs 
with the patient’s medical records at the hospital or practice, and other records relevant to 
the study. Verification will require direct access to all original records for each patient 
(e.g., clinic charts) 
 Record and report any protocol deviations not sent to the Sponsor or designee previously 
 Confirm AEs and SAEs have been documented properly in the eCRFs and confirm any 
SAEs have been forwarded to the Sponsor, and those SAEs that met criteria for reporting 
(i.e., serious adverse drug reactions) have been forwarded to the IRB/EC 
The monitor will be available between visits if the Investigator(s) or other staff needs 
information or advice. 
14.2 Data Quality Assurance 
14.2.1 
Electronic Case Report Forms and Data Management 
All data relating to the study will be recorded in the patient’s source documentation and eCRF to 
be provided by the Sponsor or designee via the electronic data capture (EDC) system. The 
eCRFs are to be completed in accordance with the data completion guidelines. Source 
documentation supporting the eCRF data should indicate the patient’s participation in the study 
and should document the dates and details of study procedures, AEs, all observations, and patient 
status. The Investigator is responsible for verifying that all data entries on the eCRFs are accurate 
and correct and ensuring that all data are entered in a timely manner, as soon as possible after 
information is collected. An explanation should be provided for all missing data. The 
Investigator must provide through EDC his or her formal approval of all the information on the 
eCRFs and changes to the eCRFs to endorse the final submitted data for the patients for which he 
or she is responsible. 
The Sponsor will retain the final eCRF data and corresponding audit trails. A copy of the final 
archival eCRF in the form of a compact disc or other electronic media will be placed in the 
Investigator’s study file. 
14.2.2 
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. 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 to the Sponsor any audit reports received. 


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14.3 Management of Protocol Amendments and Deviations 
14.3.1 
Modification of the Protocol 
Any changes in this research activity, except those necessary to remove an apparent, immediate 
hazard to the patient, must be reviewed and approved by the Sponsor or designee. Amendments 
to the protocol, other than minor clarifications and typographical corrections, must be submitted 
in writing to the Investigator’s IRB/EC and regulatory authorities for approval before patients 
can be enrolled into an amended protocol. 
14.3.2 
Protocol Deviations 
A deviation from the protocol is an unintended or unanticipated departure from the procedures or 
processes approved by the Sponsor and the IRB/EC. A major protocol deviation is any deviation 
that impacts the completeness, accuracy, and/or reliability of the study data or that may 
significantly affect a subject's rights, safety, or well-being.  
The Investigator or designee must document and explain in the patient’s source documentation 
any deviation from the approved protocol. The Investigator may implement a deviation from the 
protocol to eliminate an immediate hazard to study patients without prior IRB/EC approval. As 
soon as possible after such an occurrence, the implemented deviation, the reasons for it, and any 
proposed protocol amendments should be submitted to the IRB/EC for review and approval, to 
the Sponsor for agreement, and to the regulatory authorities, if required. 
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. 
14.4 Study Termination 
Although the Sponsor has every intention of completing the study, the Sponsor may terminate 
the study, or close an individual study site. Reasons for terminating a study or closing a site may 
include, but are not limited to, the following: 
1. The research can no longer meet its stated scientific purpose, and this assessment has 
been confirmed by the medical ethical review committee; 
2. Severe non-compliance to this protocol as judged by the investigator and/or the Sponsor; 
3. Unforeseen circumstances that prevent continuation of the research (e.g., financial issue). 
The end of the study is defined as the date on which the last patient completes the last visit 
(includes follow-up visit). 


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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. 
14.5 Final Report 
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 CSRs. 
In accordance with local regulatory requirements, a Principal Investigator will be identified for 
the approval and signoff of the clinical study report. The Principal Investigator will be provided 
reasonable access to statistical tables, figures, and relevant reports and will have the opportunity 
to review the complete study results. 
The Investigator is encouraged to share the summary results with the study patients, as 
appropriate. The study results will be posted on publicly available clinical study registers. 


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