Conditions: Huntington Disease
Allocation: RANDOMIZED | Intervention model: SEQUENTIAL
Enrollment: 47
Healthy volunteers: no

Brief summary:
This is a Phase 1b/2a multicenter, randomized, double-blind, placebo-controlled study to evaluate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of WVE-003 in adult patients with early-manifest HD who carry the targeted single nucleotide polymorphism (SNP) - SNP3.

Detailed description:

Arms:
arm 1: Placebo arm 2: Single Ascending Dose - 30mg WVE-003 arm 3: Single Ascending Dose - 60mg WVE-003 arm 4: Single Ascending Dose - 90mg WVE-003 arm 5: Placebo arm 6: Multiple Dose - 30mg WVE-003

Interventions: intervention 1: SAD: 30mg WVE-003 intervention 2: SAD: 60mg WVE-003 intervention 3: SAD: 90mg WVE-003 intervention 4: SAD: Pooled Placebo intervention 5: MD: 30mg WVE-003 intervention 6: MD: Placebo
Intervention descriptions: intervention 1: Single ascending dose of 30mg WVE-003, an allele-selective stereopure antisense oligonucleotide (ASO) intervention 2: Single ascending dose of 60mg WVE-003, an allele-selective stereopure antisense oligonucleotide (ASO) intervention 3: Single ascending dose of 90mg WVE-003, an allele-selective stereopure antisense oligonucleotide (ASO) intervention 4: Single dose of placebo intervention 5: Three doses of 30mg WVE-003 Q8WK an allele-selective stereopure, antisense oligonucleotide (ASO) intervention 6: Three doses of placebo Q8WK

Protocol document:
Prot_SAP_000.pdf: 
WVE-003-001 (Amendment 4.0) 
Phase 1b/2a Study of WVE-003 in Patients with HD 
Confidential
WVE-003 
Page 1 of 87
 
 
 
 
 
DRUG: 
WVE-003 
STUDY NUMBER(S): 
WVE-003-001 
PROTOCOL(S) TITLE: 
A Multicenter, Randomized, Double-blind, 
Placebo-controlled, Phase 1b/2a Study of WVE-003 
Administered Intrathecally in Patients With 
Huntington’s Disease  
EUDRACT NUMBER: 
2020-004556-15 
SPONSOR: 
Wave Life Sciences USA, Inc (for US)  
733 Concord Avenue  
Cambridge, MA 02138 
United States of America 
 
Wave Life Sciences UK Limited (for all other 
Ex-US) 
1 Chamberlain Square CS, 
Birmingham, B3 3AX, 
United Kingdom  
PROTOCOL AMENDMENT 
DATE: 
26 December 2022 
PROTOCOL AMENDMENT NO., 
VERSION NO. 
Amendment 4.0 (Version 5.0)  
 
CONFIDENTIAL INFORMATION 
This document is the sole property of Wave Life Sciences. This document and any and all 
information contained herein has to be considered and treated as strictly confidential. This 
document will be used only for the purpose of the disclosure herein provided. No disclosure or 
publication will be made without the prior written consent of Wave Life Sciences. 


WVE-003-001 (Amendment 4.0) 
Phase 1b/2a Study of WVE-003 in Patients with HD 
Confidential
WVE-003 
Page 2 of 87
 
 
 
CLINICAL PROTOCOL APPROVAL FORM 
SPONSOR: WAVE LIFE SCIENCES 
I have read and understand the contents of this clinical protocol for Study No. WVE-003-001 
dated 26 December 2022 (Amendment 4.0) 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. 
 
Approved By: 
 
 
 
Danlin Xu, MBBS, Ph.D 
Medical Director, Clinical Development  
Wave Life Sciences 
 
Date 
 


WVE-003-001 (Amendment 4.0) 
Phase 1b/2a Study of WVE-003 in Patients with HD 
Confidential
WVE-003 
Page 3 of 87
 
 
 
PRINCIPAL INVESTIGATOR’S AGREEMENT 
I have read and understand the contents of this clinical protocol for Study No. WVE-003-001 
dated 26 December 2022 (Amendment 4.0) 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 Harmonisation 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 
 
 
 


WVE-003-001 (Amendment 4.0) 
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Confidential
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Page 4 of 87
 
 
 
PROTOCOL SYNOPSIS 
Sponsor: 
Wave Life Sciences Ltd. 
Investigational 
Product: 
WVE-003 
Developmental 
Phase: 
EudraCT Number: 
Title of Study: A Multicenter, Randomized, Double-blind, Placebo-controlled, Phase 1b/2a Study of 
WVE-003 Administered Intrathecally in Patients With Huntington’s Disease  
Protocol Number: WVE-003-001 
Study Center(s): Approximately 30 study centers 
Objectives: 
Primary objective: 
• 
To evaluate the safety and tolerability of WVE-003 in patients with Huntington’s disease (HD) 
Secondary objectives: 
• 
To characterize the pharmacokinetics (PK) of WVE-003 in plasma  
• 
To characterize the concentration of WVE-003 in cerebrospinal fluid (CSF)  
Exploratory objectives: 
• 
To evaluate the pharmacodynamic (PD) effect of WVE-003 on the levels of mutant huntingtin 
(mHTT) protein in CSF 
• 
To evaluate the effect of WVE-003 on clinical measures of disease including the Unified 
Huntington’s Disease Rating Scale (UHDRS) and Short Problem Behaviors Assessment (PBA-s) 
• 
To evaluate the PD effects of WVE-003 on relevant biomarkers in CSF, plasma, and peripheral blood 
mononuclear cells (PBMCs) (e.g., levels of wild type huntingtin [wtHTT] protein and total huntingtin 
[tHTT] protein in CSF and neurofilament light [NfL] in CSF and plasma) 
• 
To evaluate changes from baseline in magnetic resonance imaging (MRI) of the brain 
Methodology: This is a Phase 1b/2a multicenter, randomized, double-blind, placebo-controlled study to 
evaluate the safety, tolerability, PK, and PD of WVE-003 in adult patients with early manifest HD who carry 
the targeted single nucleotide polymorphism (SNP) rs362273 (SNP3).  
To participate in the study, patients must undergo prescreening to confirm they are heterozygous for SNP3 
with the A variant on the same allele as the cytosine-adenine-guanine (CAG) triplet expansion. Prescreening 
can happen any time before Screening. The prescreening testing process to confirm the presence of SNP3 is 
expected to take up to 6 weeks. If patients meet these criteria, they will continue to the Screening visit. The 
prescreening assessment will have a separate informed consent form (ICF).   
The study will include 2 distinct periods: Period 1 to evaluate single ascending dose (SAD) cohorts and 
Period 2 to evaluate multiple ascending dose (MAD) cohorts of WVE-003. Period 2 will not be initiated 
until this Substantial Amendment to the Investigational Medicinal Product Dossier (IMPD) with the 
supportive nonclinical data is approved by the local regulatory authorities. Following this approval, the 
Sponsor intends to initiate Period 2. Patients may participate in Period 1 (SAD) and Period 2 (MAD) or 
Period 2 (MAD) only. All patients enrolled in Period 1 cohorts will have the opportunity to receive multiple 
doses in Period 2.  


WVE-003-001 (Amendment 4.0) 
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Confidential
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Sponsor: 
Wave Life Sciences Ltd. 
Investigational 
Product: 
WVE-003 
Developmental 
Phase: 
EudraCT Number: 
Cohorts in both Period 1 and Period 2 will be enrolled, randomized, and dosed in a sequential manner. 
Subsequent cohorts will not initiate until the requirements for dose escalation are met (as defined below). This 
study will utilize both a Dose Escalation Committee (DEC) and a Safety Monitoring Committee (SMC). The 
DEC will be responsible for making recommendations regarding dose escalation in Period 1, initiation of 
multiple dosing in Period 2, and subsequent dose escalation in Period 2. Decisions made by the DEC will be 
reviewed by the SMC, which makes the final recommendation. 
WVE-003 will be administered intrathecally in a volume of 20 mL of artificial CSF (aCSF).   
Period 1: 
Period 1 will evaluate SAD cohorts of WVE-003. The planned Period 1 dose cohorts were as follows. Dose 
and cohort sizes were modified following recommendations from the DEC and SMC (details provided in 
Section 2.3). 
o 
Period 1 Cohort 1 (P1C1): 6 patients (2:1 active:placebo); 30 mg  
o 
P1C2: 6 patients (2:1 active:placebo)  
If the DEC or the Sponsor determines additional single-dose data are required prior to initiating Period 2, 
subsequent SAD cohorts may be conducted. 
The first 2 patients (1:1 active:placebo) in Period 1 cohorts will be dosed and observed for 2 days in the clinic. 
If neither of these sentinel patients experiences a serious adverse event (SAE) and the Single Dose Stopping 
Criteria (as defined below) are not met, the remaining patients will be dosed sequentially. Subsequent patients 
will be observed in the clinic for 1 day after dosing. Immediately after study drug administration, all patients 
should be ambulatory and active for approximately 30 minutes postdose. The Investigator should note any 
weakness or fatigue during this period. Formal physical examinations targeting the neurological system will be 
performed postdose. Any postdose SAEs will be monitored until resolution.   
All patients will continue to be assessed for safety, PK, PD, and clinical effects through a minimum of 12 
weeks. Prior to Period 2 initiation, patients will continue to attend monthly follow-up visits through Week 24. 
After Period 2 initiation, patients can proceed to multiple dosing in Period 2 if the Week 12 visit has been 
completed.  
Subsequent SAD cohorts will not initiate until the requirements for dose escalation are met (as defined below). 
In addition, pending approval from local regulatory authorities of nonclinical data supportive of multiple 
dosing to initiate Period 2, the DEC and SMC will also determine if patients can proceed to multiple dosing in 
Period 2.  
Period 2 
Patients in Period 2 Cohort 1 (P2C1) will receive 30 mg WVE-003 or placebo administered every 8 weeks 
(Q8W). Approximately 24 patients will be enrolled in P2C1. Dose levels and cohort sizes for Period 2 
subsequent cohorts will be determined by the DEC/SMC based on previous Period 2 cohort data. Doses will be 
administered no more often than Q8W through Week 16 (maximum of 3 doses). The maximum dose in Period 
2 is not to exceed 90 mg. 
All patients from Period 1 will have the opportunity to roll into Period 2 and will receive up to 3 additional 
doses of WVE-003 or placebo. Patients will not be re-randomized and will continue to receive active drug or 
placebo based on Period 1 treatment assignment. Patients will roll into the current Period 2 cohort, irrespective 
of Period 1 dose level. 
Patients may be replaced in accordance with the requirements for dose escalation. Future DEC/SMC 
recommendations may include the addition of new Period 2 patients. All new patients in Period 2 will receive 
up to 3 doses of WVE-003 administered no more often than Q8W. 


WVE-003-001 (Amendment 4.0) 
Phase 1b/2a Study of WVE-003 in Patients with HD 
Confidential
WVE-003 
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Sponsor: 
Wave Life Sciences Ltd. 
Investigational 
Product: 
WVE-003 
Developmental 
Phase: 
EudraCT Number: 
P2C1 will be initiated pending approval from local regulatory authorities of nonclinical data supportive of 
multiple dosing to initiate Period 2, in addition to DEC and SMC approval. Subsequent MAD cohorts (P2C2 
and P2C3) will initiate when the requirements for dose escalation are met (as defined below).  
Immediately after study drug administration in any cohort, all patients should be ambulatory and active for 
approximately 30 minutes postdose on all dosing days. The Investigator should note any weakness or fatigue 
during this period. Formal physical examinations targeting the neurological system will be performed postdose 
on all dosing days. Any postdose SAEs will be monitored until resolution. Patients will attend clinic visits 
every 4 weeks (Q4W) for assessments of safety, PK, and PD. Patients in P2C1 will receive doses on Week 0, 
Week 8, and Week 16. Pending DEC/SMC recommendation, subsequent cohorts may receive doses Q8W or 
less frequently (e.g., on Week 0 and Week 12). Patients will continue to be assessed for safety, PK, PD, 
clinical effects, and MRI through a minimum of 12 weeks after their last dose.  
Dose Escalation Committee Review 
The DEC will be responsible for making recommendations regarding dose escalation in Period 1, selection of 
the initial dose level in Period 2, and subsequent dose escalation in Period 2.  
Period 1 Dose Escalation: After all patients in a Period 1 cohort have received study drug and completed 
2 weeks of postdose follow-up, the DEC will review the available safety and PK data. The DEC will determine 
if it is safe to proceed with the next SAD cohort. Additionally, at the selected dose level, the mean area under 
the plasma concentration-time curve from 0 to 24 hours (AUC0-24h) or mean maximum observed concentration 
(Cmax) should not exceed 81.6 μg*hr/mL and 19.5 μg/mL, respectively. 
Initiation of Period 2: The DEC will review the available safety and PK data and decide if Period 2 
(i.e., P2C1) can be initiated. Note that P2C1 will not be initiated until repeat-dose toxicity data have been 
submitted to and approved by the local regulatory authorities. 
Period 2 – Subsequent MAD Cohorts (P2C2 and P2C3): Once 6 patients in the current cohort have received at 
least 2 consecutive doses, the DEC will review the available safety and PK data and determine if it is safe to 
proceed with the subsequent multiple-dose cohort. The DEC may also choose to reduce the number of doses in 
a cohort or reduce frequency of dose administration based upon their review.  
Based on data review, the DEC may decide to add additional cohorts in either Period 1 or Period 2, select 
alternate dose levels (including lower doses) for any of the cohorts, or change the number of patients planned 
for a cohort. Selected dose levels will not increase by >3-fold the previous dose level and will not exceed a 
maximum dose of 168 mg in Period 1 or a maximum dose of 90 mg administered no more frequently than 
Q8W in Period 2. Additionally, at the selected dose level, the mean AUC0-24h or mean Cmax should not exceed 
81.6 µg*hr/mL or 19.5 µg/mL, the respective exposures following 15 mg Q8W in monkeys. 
The DEC will review blinded data. All recommendations of this committee will be reviewed by the SMC, 
which makes the final recommendation.  
Safety Monitoring Committee Review: In addition to reviewing the DEC’s decisions, the SMC will review 
unblinded aggregate safety data periodically and on an ad hoc basis throughout the study. The SMC will 
review any SAEs that occur in sentinel patients in order to determine if the cohort should continue or if a lower 
dose should be selected. In addition, if treatment-emergent adverse events (TEAEs) occur that meet the 
Stopping Criteria, the SMC will review the unblinded safety data and determine whether it is safe to proceed 
with the cohort or if a lower dose should be explored. 
If the stopping criteria are met at any point in the study, enrollment and dosing will be suspended until the data 
are reviewed. Similarly, if an SAE occurs in the sentinel patients in a cohort, no additional patients will be 
dosed in that cohort until the safety data are reviewed.   
Single Dose Stopping Criteria: During Period 1, dosing of patients in a cohort will be suspended: 
• 
If a single patient experiences an SAE assessed as related to study drug; 


WVE-003-001 (Amendment 4.0) 
Phase 1b/2a Study of WVE-003 in Patients with HD 
Confidential
WVE-003 
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Sponsor: 
Wave Life Sciences Ltd. 
Investigational 
Product: 
WVE-003 
Developmental 
Phase: 
EudraCT Number: 
• 
If 2 patients experience a severe TEAE that is assessed as related to study drug; or 
• 
If 4 patients experience a non-serious moderate or severe TEAE within the Medical Dictionary for 
Regulatory Activities (MedDRA) High Level Group Term (HLGT) Spinal cord and nerve root 
disorders, assessed as related to study drug. 
Notification of dose suspension for a given cohort will be made in accordance with applicable regulations. If a 
determination is made to resume the study, information will be submitted to the regulatory authorities in 
accordance with local regulations (e.g., substantial amendment) prior to restarting treatment.  
Period 2 Stopping Criteria: During Period 2, either of the following will result in a dosing halt within the 
cohort and trigger assessment by the SMC to decide the safe dose level in Period 2: 
• 
If 2 patients in a cohort experience an SAE assessed as at least possibly related to study drug. 
• 
If 2 patients in a cohort experience a non-serious severe TEAE assessed as at least possibly related to 
study drug. 
In addition, dosing will be stopped in any ongoing higher dose cohorts if the stopping rule is met in a 
lower-dose Period 2 cohort. 
Notification of dose suspension for a given cohort will be made in accordance with applicable regulations. If a 
determination is made to resume the study, information will be submitted to the regulatory authorities in 
accordance with local regulations (e.g., substantial amendment) prior to restarting treatment.   
Individual Stopping Criteria: Dosing will be stopped for an individual patient at any time in the study if: 
• 
A patient experiences a serious or intolerable adverse event (AE) that, in the Investigator’s opinion, 
requires study drug discontinuation. 
• 
A patient experiences a TEAE that is severe in intensity and related to administration of WVE-003 
(except those TEAEs associated with lumbar puncture). 
The patient will be followed up for safety per protocol. Per the Investigator’s judgement, the patient may be 
allowed to resume participation in the study if or when the event has resolved. Dosing may be resumed for 
individual patients upon recovery from the severe event and if supported by the Investigator, based on their 
assessment of the benefit/risk balance for the patient. 
Adverse event terms related to lumbar puncture and administration (e.g., procedural pain, traumatic lumbar 
puncture, or post-lumbar puncture syndrome) will be exempted from the assessment of Stopping Criteria. 
A full list of AE terms exempt from the Stopping Criteria is provided in Section 4.4.3.4.   
Number of Patients (Planned): Approximately 54 patients 
Study Population: Patients must satisfy all of the inclusion and none of the exclusion criteria to be eligible for 
the study. Patients will be required to be prescreened to determine heterozygosity at SNP3 with the A variant 
only on the same allele as the CAG triplet expansion.  
 
Inclusion Criteria: 
1. Documented ability to understand the written study ICF(s) and consent and has provided signed 
written informed consent prior to any study procedures 
2. Ambulatory male or female 
3. Age ≥25 to ≤60 years old 
4. Body mass index (BMI) ≤32 kg/m2 
5. Documented CAG triplet repeats ≥36 in the HTT gene 


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Phase 1b/2a Study of WVE-003 in Patients with HD 
Confidential
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Sponsor: 
Wave Life Sciences Ltd. 
Investigational 
Product: 
WVE-003 
Developmental 
Phase: 
EudraCT Number: 
6. Documented heterozygosity at SNP3 
7. Documented presence of the A variant of SNP3 on the same allele as the pathogenic CAG triplet 
expansion 
8. Clinical diagnostic motor features of HD, defined as UHDRS Diagnostic Confidence Score = 4  
9. UHDRS Total Functional Capacity (TFC) scores ≥9 and ≤13 
10. In the opinion of the Investigator, the patient is able to tolerate all study procedures, and is willing to 
comply with all other protocol requirements. 
11. Willingness to practice highly effective contraception for the duration of the study and for 5 months 
(i.e., 5 elimination half-lives) after the last dose of study drug, if patients or their partners are of 
childbearing potential. Non-childbearing potential and highly effective methods of contraception are 
defined in the protocol. In addition, willingness to forego sperm or ova (egg) donation for the 
duration of the study and 5 months after completion of the study. 
Exclusion Criteria: 
1. Malignancy or received treatment for malignancy, other than treated basal cell or squamous cell 
carcinoma of the skin, within the previous 5 years 
2. Positive for Hepatitis B virus (HBV) or Hepatitis C virus (HCV). 
3. Known to be positive for human immunodeficiency virus (HIV). 
4. 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 
5. Previously received tominersen   
6. Received prior treatment with viral or cellular-based gene therapy  
7. Received any other study drug, including an investigational oligonucleotide, within the past 1 year or 
5 half-lives of the drug, whichever is longer, with the exception of the following:  
a. 
Received WVE-120101 within the last 3 months (i.e., 5 half-lives); or 
b. Received WVE-120102 within the last 3 months (i.e., 5 half-lives) 
8. Implantable central nervous system device that may interfere with ability to administer study drug via 
lumbar puncture or undergo MRI scan 
9. History of substance abuse disorder (except nicotine) within 6 months prior to the Screening Visit 
10. Positive for opioids (unprescribed), cocaine, amphetamines, methadone, barbiturates, 
methamphetamine, or phencyclidine at the Screening Visit   
11. Started or changed dose for concomitant medication for the treatment of HD symptoms or psychiatric 
disorders within 30 days prior to the Screening Visit (concomitant medications that have been 
administered on a stable regimen for ≥30 days are permitted) 
12. 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 
13. Clinically significant laboratory abnormality at Screening 
14. Clinically significant abnormality at Screening electrocardiogram (ECG), including but not 
necessarily 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: 
Wave Life Sciences Ltd. 
Investigational 
Product: 
WVE-003 
Developmental 
Phase: 
EudraCT Number: 
15. 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. Mental status, psychiatric medical history, and eligibility for the study must be 
documented in the screening questionnaire.  
16. Bone, spine, bleeding, or other disorder that exposes the patient to risk of injury or unsuccessful 
lumbar puncture 
17. Inability to undergo brain MRI (with or without sedation)   
18. Deemed to be at significant risk for suicidal behavior based on any the following criteria: 
a. 
The opinion of the Investigator 
b. Answers “yes” to Actual Suicide Attempts or Suicidal Behaviors in the Suicidal Behaviors 
section of the Columbia-Suicide Severity Rating Scale (C-SSRS) with reference to a 2-year 
period prior to the Screening Visit 
c. 
Answers “yes” on any items in the Suicidal Ideation section of the C-SSRS with reference to 
a 6-month period prior to the Screening Visit 
d. Answers “yes” on any items in the Suicidal Ideation section of the C-SSRS at the Baseline 
Visit since the last visit (Screening Visit) 
19. 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 
20. History of hypersensitivity to other antisense oligonucleotides and any other drug that in the opinion 
of the investigator may preclude study participation. 
Investigational Product, Dose, Route, Regimen:  
The currently planned starting dose level in Period 1 is 30 mg. The dose levels in subsequent Period 1 cohorts 
and Period 2 will be determined based on the findings in Period 1 and pending repeat-dose toxicity data from 
the GLP studies. The dose levels will not exceed a maximum dose of 168 mg in Period 1 or 90 mg in Period 2. 
In Period 2, doses will be administered no more often than Q8W from Week 0 (first dose) through Week 16 
(3 total doses).   
WVE-003 will be provided as lyophilized powder for reconstitution and dilution for IT injection. WVE-003 
for injection will be prepared by reconstituting and diluting the lyophilized powder with aCSF supplied by the 
Sponsor.  
Reference Therapy, Dose, Route, Regimen:  
Placebo will be aCSF provided by the Sponsor. It will be a sterile, preservative-free solution. Placebo will be 
visually identical in appearance to the WVE-003 injection solution and administered intrathecally in order to 
maintain the blind. Placebo will be administered in a volume of 20 mL. 
Study Duration:  
Period 1: This period will consist of a single dose and up to 24 weeks of postdose follow-up. 
Period 2: This period will consist of up to 16 weeks of treatment and a minimum of 12 weeks of follow-up. 
Endpoints:  
Safety: 


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Sponsor: 
Wave Life Sciences Ltd. 
Investigational 
Product: 
WVE-003 
Developmental 
Phase: 
EudraCT Number: 
Adverse events, concomitant medications, physical examinations including detailed neurological examination, 
vital signs, weight, 12-lead ECGs, clinical laboratory evaluations (including clinical chemistry, hematology, 
and urinalysis), CSF safety evaluations, MRI of the brain, and C-SSRS 
Pharmacokinetics: 
• 
Pharmacokinetic parameters of WVE-003 in plasma  
• 
Concentration of WVE-003 in CSF   
Pharmacodynamics: 
• 
Change from baseline in the level of mHTT protein in CSF  
• 
Change from baseline in the level of wtHTT protein in CSF  
• 
Change from baseline in the level of tHTT protein in CSF  
• 
Change from baseline in the level of NfL in CSF  
• 
Change from baseline in the level of exploratory biomarkers in CSF, plasma, and/or PBMCs 
Clinical Effects Endpoint(s): 
• 
Change from baseline in the UHDRS TFC 
• 
Change from baseline in UHDRS total motor score 
• 
Change from baseline in the UHDRS independence scale 
• 
Change from baseline in Symbol Digit Modalities Test 
• 
Change from baseline in Stroop word reading test 
• 
Change from baseline in the composite UHDRS 
• 
Change from baseline in the PBA-s 
• 
Changes from baseline in MRI of the brain 
Statistical Methods:  
The sample size was not calculated on the basis of statistical hypothesis testing; however, the number of 
patients is sufficient for a Phase 1b/2a assessment of safety, tolerability, PK, and early measures of PD and 
clinical effects.   
Summary statistics (n, mean, standard deviation [SD], median, minimum and maximum values for continuous 
variables, and number [%] of patients in each category for categorical variables) will be provided by dose 
group and visit.  
The change from baseline for PD and clinical effects endpoints will be summarized using a mixed model for 
repeated measures (MMRM). The MMRM will be used to construct 95% confidence intervals and to test for 
differences between dose groups and placebo.   
Treatment-emergent AEs (TEAEs) and treatment-emergent SAEs will be summarized for each dose group 
based on MedDRA coding of verbatim terms reported by investigators. 
 


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TABLE OF CONTENTS 
Clinical Protocol Approval Form .....................................................................................2 
Principal Investigator’s Agreement .................................................................................3 
Protocol Synopsis ...............................................................................................................4 
Table of Contents .............................................................................................................11 
List of Tables ....................................................................................................................14 
List of Figures ...................................................................................................................14 
List of Abbreviations .......................................................................................................15 
1 
Introduction ...............................................................................................................18 
1.1 
Huntington’s Disease ...........................................................................................18 
1.2 
Investigational Product WVE-003......................................................................18 
1.3 
Nonclinical Data ...................................................................................................19 
1.4 
Clinical Experience ..............................................................................................21 
2 
Rationale for the Study ............................................................................................21 
2.1 
Rationale for the Doses and the Dosing Regimen .............................................22 
2.2 
Anticipated Benefit/Risk .....................................................................................24 
2.3 
Current Status of the Study and Dosing Paradigms as Recommended by the 
DEC and SMC ......................................................................................................24 
3 
Study Objectives .......................................................................................................25 
4 
Study Design ..............................................................................................................25 
4.1 
Study Design Overview........................................................................................25 
4.1.1 
Prescreening Phase ........................................................................................29 
4.1.2 
Screening Phase ..............................................................................................29 
4.1.3 
Period 1 (Single-ascending-dose Period) ......................................................30 
4.1.4 
Period 2 (Multiple-ascending-dose Period) .................................................31 
4.1.5 
Early Termination Visit ................................................................................32 
4.2 
Schedule of Assessments ......................................................................................32 
4.3 
Study Endpoints ...................................................................................................48 
4.4 
Safety Considerations ..........................................................................................49 
4.4.1 
Dose Escalation Committee Review .............................................................49 
4.4.2 
Safety Monitoring Committee Review .........................................................49 
4.4.3 
Stopping Criteria ...........................................................................................50 
4.4.4 
Communication of Emergent Safety Concerns ...........................................52 
4.4.5 
Considerations Due to COVID-19 Pandemic ..............................................52 
5 
Patient Selection and Withdrawal Criteria ............................................................53 
5.1 
Inclusion Criteria .................................................................................................53 
5.2 
Exclusion Criteria ................................................................................................54 
5.2.1 
Additional Study Restrictions .......................................................................56 
5.3 
Withdrawal and Discontinuation .......................................................................57 
5.3.1 
Withdrawal of Patients From the Study ......................................................57 
5.3.2 
Discontinuation of Study Drug .....................................................................57 
5.3.3 
Lost to Follow-up ...........................................................................................58 
5.3.4 
Replacements ..................................................................................................58 
6 
Investigational Drug and Placebo ...........................................................................58 


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6.1 
Method of Assigning Patients to Investigational Drug or Placebo ..................58 
6.2 
Dose and Investigational Drug/Placebo Administration ..................................59 
6.2.1 
Identity of Investigational Drug ...................................................................59 
6.2.2 
Administration of Investigational Drug .......................................................59 
6.3 
Treatment Compliance ........................................................................................60 
6.4 
Management of Clinical Supplies .......................................................................60 
6.4.1 
Investigational Drug Packaging and Storage ..............................................60 
6.4.2 
Study Drug Accountability............................................................................60 
6.4.3 
Other Supplies ................................................................................................61 
7 
Blinding and Randomization ...................................................................................61 
7.1 
Blinding .................................................................................................................61 
7.2 
Breaking the Blind ...............................................................................................61 
7.2.1 
Unblinding for Medical Emergency .............................................................61 
7.2.2 
Recording the Unblinding .............................................................................61 
7.3 
Randomization .....................................................................................................62 
8 
Methods of Assessment and Endpoints...................................................................62 
8.1 
Prescreening Assessments ...................................................................................62 
8.2 
Safety Assessments ...............................................................................................63 
8.2.1 
Medical History and Demographics .............................................................63 
8.2.2 
Prior and Concomitant Medications ............................................................64 
8.2.3 
Physical Examination ....................................................................................64 
8.2.4 
Height and Weight .........................................................................................64 
8.2.5 
Vital Signs (Blood Pressure, Heart Rate and Temperature) .....................64 
8.2.6 
12-Lead ECG ..................................................................................................65 
8.2.7 
Clinical Laboratory Evaluations ..................................................................65 
8.2.8 
Cerebrospinal Fluid Safety Laboratory Evaluation ...................................66 
8.2.9 
Suicidality Assessment (Columbia-Suicide Severity Rating Scale) ...........66 
8.2.10 
Pregnancy Testing ..........................................................................................67 
8.2.11 
Drug Screening ...............................................................................................67 
8.3 
Pharmacokinetic Assessments ............................................................................67 
8.4 
Pharmacodynamic Assessments .........................................................................68 
8.5 
Immunogenicity Assessments .............................................................................68 
8.6 
Magnetic Resonance Imaging .............................................................................69 
8.7 
Clinical Effects .....................................................................................................69 
8.7.1 
Unified Huntington’s Disease Rating Scale .................................................69 
8.7.2 
Short Problem Behaviors Assessment ..........................................................70 
9 
Adverse Events ..........................................................................................................70 
9.1 
Eliciting and Documenting Adverse Events ......................................................70 
9.2 
Definitions of Adverse Event Severity and Relationship to Study Drug ........71 
9.2.1 
Severity............................................................................................................71 
9.2.2 
Relationship to Study Drug and/or Study Procedure .................................71 
9.3 
Serious Adverse Events .......................................................................................72 
9.3.1 
Serious Adverse Event Criteria ....................................................................72 
9.3.2 
Suspected Unexpected Serious Adverse Reactions .....................................73 
9.3.3 
Serious Adverse Event Follow-up.................................................................73 


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9.3.4 
Serious Adverse Event Reporting.................................................................73 
9.4 
Overdose ...............................................................................................................74 
10 Pregnancies ................................................................................................................75 
11 Statistical Methods ....................................................................................................75 
11.1 
Sample Size Determination .................................................................................75 
11.2 
Disposition of Patients .........................................................................................75 
11.2.1 
Analysis Populations ......................................................................................75 
11.3 
Statistical Methods ...............................................................................................76 
11.3.1 
Study Drug Exposure and Compliance .......................................................76 
11.3.2 
Analysis of Clinical Effects Endpoints .........................................................76 
11.3.3 
Analysis of Pharmacodynamic Endpoints ...................................................76 
11.3.4 
Analysis of Safety Data ..................................................................................76 
11.3.5 
Analysis of Pharmacokinetic Variables .......................................................77 
11.3.6 
Interim Analyses ............................................................................................78 
12 Regulatory, Ethical, and Legal Obligations ...........................................................78 
12.1 
Declaration of Helsinki ........................................................................................78 
12.2 
Good Clinical Practice .........................................................................................78 
12.3 
Institutional Review Boards/Ethics Committees...............................................78 
12.4 
Informed Consent Forms ....................................................................................79 
12.5 
Privacy ..................................................................................................................79 
13 Investigator’s Obligations ........................................................................................79 
13.1 
Confidentiality ......................................................................................................79 
13.2 
Investigator Documentation ................................................................................80 
13.3 
Study Conduct ......................................................................................................80 
13.4 
Adherence to Protocol .........................................................................................80 
13.5 
Adverse Events and Study Report Requirements.............................................81 
13.6 
Investigator’s Final Report .................................................................................81 
13.7 
Records Retention ................................................................................................81 
13.8 
Publications ..........................................................................................................81 
14 Study Committees .....................................................................................................81 
14.1 
Safety Monitoring Committee ............................................................................81 
14.2 
Dose Escalation Committee .................................................................................82 
14.3 
Clinical Advisory Committee ..............................................................................82 
14.4 
Publications Committee.......................................................................................82 
15 Study Management ...................................................................................................82 
15.1 
Monitoring ............................................................................................................82 
15.1.1 
Monitoring of the Study ................................................................................82 
15.2 
Data Quality Assurance .......................................................................................83 
15.2.1 
Electronic Case Report Forms and Data Management ..............................83 
15.2.2 
Inspection of Records ....................................................................................83 
15.3 
Management of Protocol Amendments and Deviations ...................................84 
15.3.1 
Modification of the Protocol .........................................................................84 
15.3.2 
Protocol Deviations ........................................................................................84 
15.4 
Study Termination ...............................................................................................84 
15.5 
Final Report ..........................................................................................................85 


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16 References ..................................................................................................................85 
 
LIST OF TABLES 
Table 1 
Schedule of Assessments (Period 1) ..............................................................34 
Table 2 
Detailed Time Points for Selected Assessments (Period 1) .........................39 
Table 3 
Schedule of Assessments (Period 2) ..............................................................41 
Table 4 
Detailed Time Points for Selected Assessments (Period 2) .........................46 
Table 5 
Adverse Event Preferred Terms Exempted From Stopping Criteria .......51 
Table 6 
Clinical Laboratory Assessments .................................................................66 
Table 7 
Definitions of AE Severity Criteria ..............................................................71 
Table 8 
Guidelines for Determining the Relationship (if Any) Between Adverse 
Event and the Study Drug and/or Study Procedure .........................................72 
Table 9 
Plasma Pharmacokinetic Parameters of WVE-003 ....................................78 
LIST OF FIGURES 
Figure 1 
Schematic of Study Design ......................................................................27 
 
 
 


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LIST OF ABBREVIATIONS  
Abbreviation 
Definition 
aCSF 
artificial cerebrospinal fluid 
AE 
adverse event 
ALT 
alanine aminotransferase 
aPTT 
activated partial thromboplastin time 
AS LR-PCR 
allele-specific long-range polymerase chain reaction  
ASO 
antisense oligonucleotide 
AST 
aspartate aminotransferase 
AUC 
area under the concentration-time curve 
AUC0-24h 
area under the plasma concentration-time curve from 0 to 24 hours 
BACHD 
bacterial artificial chromosome (BAC)-mediated transgenic Huntington’s disease 
BMI 
body mass index 
CAG 
cytosine-adenine-guanine  
CBC 
complete blood count 
CE 
capillary electrophoresis 
CFR 
Code of Federal Regulations 
Cmax 
maximum observed concentration 
CNS 
central nervous system  
COVID-19 
Coronavirus Disease 2019 
CRO 
contract research organization 
CRP 
C-reactive protein 
CSF 
cerebrospinal fluid 
CSR 
clinical study report 
C-SSRS 
Columbia-Suicide Severity Rating Scale  
CTA 
Clinical Trial Application 
CTCAE 
Common Terminology Criteria for Adverse Events  
DEC 
Dose Escalation Committee 
DNA 
deoxyribonucleic acid 
EC 
Ethics Committee 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EHDN 
European Huntington’s Disease Network  


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Abbreviation 
Definition 
EOS 
end of study 
ET 
early termination 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 
HBsAg 
hepatitis B surface antigen 
HBV 
Hepatitis B virus  
HCV 
Hepatitis C virus  
HD  
Huntington’s disease 
HED 
human equivalent dose 
HIV 
human immunodeficiency virus  
HLGT 
High Level Group Term  
HTT 
Huntingtin 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
ICV 
intracerebroventricular 
IMPD 
Investigational Medicinal Product Dossier  
IRB 
Institutional Review Board 
IRT 
interactive response technology 
IT 
intrathecal 
IUD 
intrauterine device 
IUS 
intrauterine hormone-releasing system 
MAD 
multiple ascending dose 
MedDRA 
Medical Dictionary for Regulatory Activities  
mHTT 
mutant huntingtin 
MMRM 
mixed model for repeated measures  
MRI 
magnetic resonance imaging  
mRNA 
messenger ribonucleic acid 
NCI 
National Cancer Institute 
NfL 
neurofilament light 
NOAEL 
no-observed-adverse-effect-level 
PBA-HD 
Problem Behaviors Assessment for HD  


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Abbreviation 
Definition 
PBA-s 
Short Problem Behaviors Assessment  
PBMC 
peripheral blood mononuclear cell 
PD 
pharmacodynamics(s) 
PK 
pharmacokinetic(s) 
PT 
Preferred Term 
PxCx 
Period x Cohort x 
Q4W 
every 4 weeks 
Q8W 
every 8 weeks 
QTc 
QT interval corrected for heart rate 
RNA 
ribonucleic acid 
RP-PCR 
repeat primed polymerase chain reaction 
RSI 
reference safety information 
SAD 
single ascending dose 
SAE 
serious adverse event 
SD 
standard deviation 
SDMT 
Symbol Digit Modalities Test  
SMC 
Safety Monitoring Committee 
SNP 
single nucleotide polymorphism 
SNP3 
single nucleotide polymorphism rs362273 
SOC 
system organ class 
SOP 
standard operating procedure 
SUSAR 
suspected unexpected serious adverse reaction 
TEAE 
treatment-emergent adverse event 
TFC 
Total Functional Capacity 
tHTT 
total huntingtin 
t1/2 
half-life 
tmax  
Time of occurrence of Cmax  
UHDRS 
Unified Huntington’s Disease Rating Scale  
wtHTT 
wild type huntingtin 
 
 
 


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1 INTRODUCTION 
1.1 
Huntington’s Disease 
Huntington’s disease (HD) 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, one of the most visually prominent symptoms of this 
disease is chorea. 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 50 years1. 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. As symptoms progress, individuals become increasingly or totally 
dependent on others for care. Suicidal ideation is increased in the early stages of the disease, 
likely associated with a perceived loss of independence, and patients with HD have a 
significantly higher rate of suicide as compared with a normal healthy adult population (138 per 
100,000 and 12 to 13 per 100,000 persons per year, respectively)3,4.  
Prevalence in Europe, North America, and Australia is approximately 6 per 100,0005. 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 affecting the 
dopamine pathways, which modulate the movement disorder2. 
Huntington’s disease is caused by known mutations on a single gene, 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, it is believed to be a scaffolding protein that helps 
coordinate other proteins and cellular functions8, and some studies have shown that it may play 
an important role in neuronal functions7,9-11. However, expansion in the CAG triplet repeat in the 
HTT gene results in production of the mutant huntingtin (mHTT) protein. Mutant HTT is thought 
to cause disease by a predominant toxic gain-of-function mechanism8. In nonclinical studies, 
lowering the level of mHTT protein as measured in the cerebrospinal fluid (CSF) has been 
demonstrated to be therapeutic12,13. Therefore, a drug that can silence the mHTT gene transcript 
while leaving the wild type allele intact may be able to slow, stop, or even reverse the course of 
HD14. 
1.2 
Investigational Product WVE-003 
WVE-003 is a stereopure antisense oligonucleotide (ASO) being developed to selectively target 
the mHTT transcript leaving the wtHTT transcript relatively unaffected. WVE-003 specifically 
targets the mHTT messenger RNA (mRNA) transcript at the A variant of single nucleotide 
polymorphism (SNP) rs362273 (SNP3). An SNP is a single nucleotide variation in the 
deoxyribonucleic acid (DNA) that can be associated with a mutated gene. One of the most 
frequent SNPs in the mHTT gene is SNP3, which has been shown to be present in approximately 
40% to 45% of patients with HD15,16. By selectively targeting the SNP3 variant associated with 


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the pathogenic CAG expansion (≥36 repeats), treatment with WVE-003 should result in selective 
reduction of mHTT transcript and protein levels. 
Oligonucleotides are a type of nucleic acid molecule synthesized from chemically modified 
ribonucleic acid (RNA) and/or DNA monomer building blocks17,18. WVE-003 contains 
phosphodiester and phosphorothioate internucleotide linkages, as well as a novel backbone 
chemistry: phosphoramidate linkages. Unlike phosphorothioate diester or phosphodiester 
linkages, which are both permanently negatively charged, the stereodefined phosphoramidate 
used in WVE-003 ([1,3-dimethylimidazolidin-2-ylidene] phosphoramidate diester) is not 
charged at physiological pH. It is hypothesized that charge modulation of ASOs could enhance 
cellular uptake19,20.  
1.3 
Nonclinical Data 
Based on the results of the nonclinical studies, WVE-003 has promise as a disease-modifying 
agent for the treatment of patients with HD. In vitro pharmacology studies confirmed that 
WVE-003 demonstrates selective knockdown of the mHTT mRNA and protein through cleavage 
of the mutant allele versus the wild type allele. This selective knockdown results in greater 
reduction of the mHTT protein over wtHTT protein produced by this RNA and, thus, may limit 
the unintended, potentially deleterious effects of decreasing wtHTT7,9-11. In vivo studies utilized 
the bacterial artificial chromosome (BAC)-mediated transgenic Huntington’s disease (BACHD) 
transgenic mouse model, which demonstrated target engagement by dose-dependent reductions 
in HTT transcripts in the striatum and cortex after intracerebroventricular (ICV) administration 
of WVE-003 that was sustained for 12 weeks. The optimal dose and dosing frequency for 
efficacy in humans was modeled using data from the BACHD mouse and cynomolgus monkey 
and will be further explored during clinical development. 
The absorption, distribution, and metabolism of WVE-003 were characterized in in vitro and/or 
in vivo studies after IT administration in rats and monkeys and following ICV administration in 
BACHD mice to support clinical development of WVE-003. No gender difference was observed 
in plasma, CSF, or tissue pharmacokinetic (PK) profiles. There were no apparent systemic 
accumulation based on plasma area under the concentration-time curve (AUC) or maximum 
observed concentration (Cmax) with every-other-week, every 4 weeks (Q4W), or every 8 weeks 
(Q8W) repeated dosing in the monkey. 
In vitro, WVE-003 is highly protein bound in mouse, rat, monkey, and human plasma (>96%). 
WVE-003 demonstrated 34.1% and 20.6% CSF protein binding in monkey and human CSF, 
respectively. WVE-003 was metabolized via nucleases to chain-shortened metabolites including 
3´N-10, from both the 3´ or 5´-end truncated metabolites in mouse, and 3´N-10, 5´N-3, and 5´N-
10 chain shortened metabolites in the cynomolgus monkey. The 3´N-10 metabolite was the most 
abundant metabolite in both mouse and monkey. 
The results of the toxicity studies conducted to date indicate that the pertinent findings associated 
with WVE-003 include non-adverse findings of transient lethargy, weakness, or hindlimb 
dysfunction in the mouse (≥0.1 mg) and rat (≥0.5 mg), which resolved within 24 to 48 hours.  


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Histopathology findings in the rat consisted of minimal perivascular vacuolated macrophages in 
various tissues, including the brain and thoracic and/or lumbar spinal cord, and vacuolation of 
macrophages between the nerve fibers at the injection site, nerve roots of the lumbar spinal cord, 
nerve fibers of the trigeminal nerve and dorsal nerve roots (cervical, thoracic, and lumbar) at IT 
injections ≥0.1 mg. These changes are known to occur following the administration of a variety 
of large molecular weight test articles to the IT space21,22. Also, minimal to mild non-adverse 
nerve fiber degeneration was observed at the injection site and/or in the lumbar spinal cord 
(nerve roots) in males and females at all dose levels as well as in the sciatic nerve at ≥0.3 mg; 
these findings were not fully reversible following a 13-week recovery period with the exception 
of cervical and thoracic spinal cord, and trigeminal nerve. The minimal CNS nerve and nerve 
root degeneration in the rat may be procedural-related23-25. In a non-Good Laboratory Practice 
(GLP) study, 1 animal administered 1.5 mg WVE-003 had minimal multifocal necrosis limited 
to the cerebellar cortex that was considered possibly WVE-003-related. In the monkey, no 
histopathology findings were noted in the CNS tissues following a single dose up to 15 mg. 
An increased incidence of reversible minimal single cell necrosis was observed in the thymus of 
female rats at 0.9 mg. The underlying cause for the minimal single cell necrosis is not fully 
understood; however, it was considered non-adverse due to the minimal, reversible nature and 
was only observed in rats. There were no macroscopic or microscopic findings in the thymus in 
monkeys to date; therefore, the relevance to humans is unknown. Known class effects of 
oligonucleotides were observed in the rat, including minimal tubular basophilic granules in the 
kidney in males at 0.9 mg and in females at ≥0.3 mg and mild, reversible tubular degeneration in 
1 male at 0.9 mg26.  
In the monkey, basophilic granules in renal tubular epithelium (≥3 mg) and vacuolation of 
sinusoidal liver cells (≥9 mg) were observed. These findings were non-adverse as there were no 
associated degenerative findings. Similar to the findings in the rat, these histopathology findings 
are consistent with the class effects of oligonucleotide compounds26.   
In the monkey, following repeat doses of WVE-003 (0, 5, 15, or 32 mg) up to 13 weeks 
administered on Days 1, 15, 29, 57, and 85, PK characteristics and histopathology results 
precluded determination of a no-observed-adverse-effect-level (NOAEL) 
(Covance Study 8441773). A second repeat-dose study evaluating less frequent administration of 
WVE-003 (0, 1, 3, 7, or 15 mg Q8W) is ongoing. No mortality occurred through the end of the 
recovery phase, and no adverse findings were observed through the dosing phase (Day 120). 
The interim NOAEL was determined to be 15 mg Q8W (Labcorp Study 8487043).  
Evaluation of off-target effects via hybridization to the human genome showed some homology 
with 18/20 base pair matches (HIC ZBTB transcriptional repressor 1, a tumor suppressor that is 
not expressed in the CNS, and RIC8 guanine nucleotide exchange factor B, which is ubiquitously 
expressed); however, a low potential for off-target effects is expected at clinically relevant 
concentrations based on known expression patterns in humans, binding energies in comparison 
to on-target HTT (estimated ΔGs equal to 75% to 80% of the target HTT gene), known function, 
and relative off-target WVE-003 half maximal inhibitory concentrations (IC50) that far exceed 
the observed and projected maximum CNS tissue concentrations at the top dose. 


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WVE-003 demonstrated minimal potential for the recognized toxicities of phosphorothioate 
oligonucleotides, such as pro-inflammatory effects, activated partial thromboplastin time(aPTT) 
prolongation, thrombocytopenia, hepatotoxicity, or nephrotoxicity26,27. In addition, WVE-003 
was not associated with any other toxicities, including genotoxicity or effects on cardiovascular 
or respiratory function.   
1.4 
Clinical Experience 
This will be the first clinical study conducted with WVE-003. 
2 RATIONALE FOR THE STUDY 
This initial clinical study with WVE-003 was designed to evaluate the safety and tolerability of 
single ascending dose (SAD) cohorts followed by multiple ascending dose (MAD) cohorts. 
Information on the safety, tolerability, PK, pharmacodynamics (PD), and clinical effects of 
WVE-003 will inform dose selection for subsequent clinical studies.  
As the primary endpoint is the safety and tolerability of WVE-003, placebo is the most 
appropriate comparator for this study. It is also important to distinguish between drug-related and 
procedure-related adverse events, which is difficult in a limited number of patients. Therefore, 
performing lumbar punctures in patients receiving placebo will be crucially important for 
comparison. Furthermore, one vital objective is to evaluate the biologic response to the study 
drug, which will be measured using mHTT levels in CSF. It is important to understand the 
natural variability in the level of mHTT in CSF within a single patient as well as between 
patients in order to accurately interpret these mHTT measurements. In addition to trying to 
establish whether or not mHTT lowering occurred, demonstration of dose response would be 
important in the planning of subsequent studies. Together with exposure data, mHTT lowering at 
different doses will form the basis of modeling to identify the optimal dose(s) and dosing interval 
in subsequent studies.  
The volume of injection with artificial CSF (aCSF) is 20 mL, and an equivalent volume of CSF 
will be withdrawn for bioanalysis and to maintain CSF pressure. It is a relatively small volume 
compared to the total volume of CSF in humans, which is approximately 150 mL (range – 130 to 
160 mL), with normal production rate of CSF being approximately 500 mL per day28. 
As this is a safety and tolerability study, HD patients who are in the early stages of disease, 
characterized by mild or no incapacity, will be selected in order to characterize the safety and 
tolerability of WVE 003. Early stage HD patients are capable of informed consent as evidence by 
their near normal functional capacity. It is necessary to conduct this study in patients, rather than 
in healthy volunteers, for 2 reasons. First, a better understanding of the safety and effects of 
WVE-003 in its intended target population will be achieved in patients because the intended 
target of WVE-003 is not present in healthy volunteers. Second, WVE-003 must be administered 
via IT administration, and consideration of the balance between risk and benefit justifies 
investigation in a patient population only. Although assessment of safety is the primary objective 
of this study, HD patients who enroll in this study will be relatively early in the manifest disease 


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process and may experience benefit from the investigational treatment if it addresses the primary 
pathogenesis of the disease. 
Although evaluation of safety and tolerability is the primary objective of this study, HD patients 
who enroll in this study will be relatively early in the manifest disease process and may 
experience benefit from the investigational treatment if it addresses the primary pathogenesis of 
the disease. 
Period 1 will evaluate the initial safety and tolerability of single doses of WVE-003. In an effort 
to enable patients to derive additional benefit through repeated exposure to WVE-003, all 
patients from the SAD part of the study (Period 1) will be allowed to roll into Period 2, during 
which they will receive up to 3 additional doses of WVE-003. Additional new patients may be 
enrolled directly into Period 2, which will evaluate multiple ascending dose (MAD) cohorts. 
Patients will have a minimum 12-week washout period between Periods 1 and Period 2. Based 
on the approximate WVE-003 CSF half-life (t1/2) of 6 to 20 days in cynomolgus monkeys, the 
washout period of 12 weeks is considered sufficient (approximately 5 half-lives).  
The follow-up in Period 1 was extended up to 24 weeks based on PK/PD analyses following 
single doses of WVE-003, after which mean reductions in CSF mHTT from baseline of 22% 
were observed. The extension of the follow-up period provides the opportunity to obtain 
additional plasma and follow-up imaging samples prior to participation in Period 2. Patients are 
only required to complete Period 1 Day 85 prior to rollover into Period 2.  
This protocol details the complete study design and assessments to be performed in both Period 1 
and Period 2. However, Period 2 of the study (multi-dose part) will not be initiated until this 
substantial amendment to the Investigational Medicinal Product Dossier (IMPD; or regional 
equivalent thereto) containing supportive repeat-dose toxicity data is approved by the local 
regulatory authorities. By taking this approach, it provides full transparency regarding the 
availability of repeat-dose exposure for patients enrolled in the SAD period of the study (Period 
1) at the time of informed consent. In addition, this approach will help to minimize any gap 
between Periods 1 and 2 for patients enrolled in the SAD period. The Sponsor will communicate 
this approval (in writing) directly to the study sites for initiation of Period 2. 
The Sponsor plans to initiate an open-label extension study providing treatment for up to 2 years 
for patients who complete the Phase 1b/2a study. The open-label extension study will be 
submitted as a separate Clinical Trial Application (CTA) at a later date, when the required 
chronic toxicity data become available. This will ensure all patients will have access to a 
potentially therapeutic treatment.  
2.1 
Rationale for the Doses and the Dosing Regimen 
This study is designed to evaluate the safety, tolerability, PK, PD response, and clinical effect 
associated with WVE-003 and to support its further clinical development. The selection of the 
starting and subsequent doses and dose frequency was based on multiple factors, including 
projected human exposure and target engagement (mHTT mRNA knockdown) based on in vivo 
studies in animals, and the NOAEL provided by the GLP toxicity studies. 


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Allometric scaling was applied to project human tissue PK profiles using data from cynomolgus 
monkeys, using a scaling factor based on CSF volume across species29-31. The relationship 
between WVE-003 tissue concentration and mHTT mRNA knockdown was established in a 
BACHD mouse model. A starting single dose of 30 mg was expected to provide pharmacologic 
activity. This dose level is associated with a 5.6-fold safety margin based on the human 
equivalent dose (HED, based on CSF volume29-31) of the NOAEL observed in monkeys (15 mg; 
HED of 168 mg) and a 16.8-fold safety margin based on the HED of the NOAEL observed in 
rats (0.9 mg; HED of 504 mg). This dose was selected to adequately balance the risk/benefit for 
patients.  
In Period 1, the maximum dose was not to exceed the lowest HED (168 mg) of the NOAEL from 
the single-dose GLP studies. Higher doses are expected to provide greater mHTT mRNA 
knockdown and thus have more potential for therapeutic benefit. The Sponsor reviewed available 
safety, tolerability, and PK data from prior dosed cohort(s) in Period 1 before selecting 
subsequent higher single doses for evaluation. Details on the criteria for dose selection are 
presented in Section 4.4.1.1. 
Based on an unblinded review of available safety, PK, and PD data from Period 1, the Dose 
Escalation Committee (DEC)/Safety Monitoring Committee (SMC) recommended initiation of 
Period 2 with a dose level and frequency of 30 mg administered Q8W for Period 2 Cohort 1 
(P2C1). WVE-003 showed an acceptable safety profile in HD patients who received a single 
dose of WVE-003 up to 90 mg in Period 1. In addition, the mHTT target engagement was 
observed following single doses of WVE-003, after which mean reductions in CSF mHTT from 
baseline of 22% were observed. Based on single dose PK in Period 1, 30 mg and Q8W dosing 
interval is projected to minimize potential drug accumulation while potentially enabling greater 
target engagement as compared to single dose. The total dose to be administered in P2C1 is 
90 mg, equivalent to the highest single dose of 90 mg tested in Period 1, which appears to be safe 
and well tolerated. The findings from a 17-week toxicology study in the monkey (Study 
8487043; ongoing, recovery phase) fully support the dose regimen of 30 mg Q8W. There is a 
projected plasma safety margin of 30.6-fold for area under the plasma concentration-time curve 
from 0 to 24 hours (AUC0-24h) and 76.5-fold for Cmax. Furthermore, there is a 5.6-fold margin 
based on HED. The exposure margin was calculated based on single dose 30 mg data in Period 1 
because no accumulation is expected in humans. 
Safety, tolerability, PD, and PK data, in addition to target engagement data from clinical and 
nonclinical studies, will be used to select the subsequent doses and frequencies for the 
multiple-dose period (Period 2) of the study. Details on these criteria are presented in 
Section 4.4.1.3 (subsequent dose selection in Period 2). The maximum dose in Period 2 is not to 
exceed 90 mg. This dose is well below 168 mg, the HED of the NOAEL from the repeat dose 
(Q8W) toxicology study in cynomolgus monkeys (Study 8487043, NOAEL = 15 mg). WVE-003 
will be administered no more often than Q8W over 16 weeks. Additionally, at the selected dose 
level, the mean AUC0-24h or mean Cmax should not exceed 81.6 µg*hr/mL or 19.5 µg/mL, the 
respective exposures following 15 mg Q8W in monkeys (Study 8487043). There is a projected 
plasma safety margin of 7.5-fold for AUC0-24h and 12.0-fold for Cmax at the 90 mg dose level. 


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The Sponsor will continue to evaluate available nonclinical and clinical data to optimize the dose 
level and frequency in Period 2. WVE-003 will not be administered more frequently than Q8W 
through Week 16, for a maximum of 3 total doses.  
2.2 
Anticipated Benefit/Risk  
Huntington’s disease is a rare, progressive neurological disease1. Currently available treatments 
for HD only mitigate symptoms and do not affect the underlying HD pathology, the disease 
course, or life expectancy after diagnosis of HD 32. No approved treatments exist that can cure, 
slow, or reverse the course of HD. Based on the results of the nonclinical studies, WVE-003 has 
promise as a disease-modifying agent for the treatment of patients with HD. Target engagement 
was demonstrated both in vitro and in vivo. Nonclinical studies conducted in rats and monkeys 
yielded no toxicologically meaningful findings that would prevent initiation of clinical studies in 
HD patients. Intrathecal administration of WVE-003 was associated with transient or non-
adverse neurological effects. WVE-003 was not associated with any other toxicities that are 
translatable to humans, including the recognized toxicities of PS and OMe oligonucleotides, and 
no novel toxicities have emerged to date that are associated with the stereodefined 
phosphoramidate (PN) diester linkage. 
2.3 
Current Status of the Study and Dosing Paradigms as Recommended by 
the DEC and SMC 
This is an adaptive study designed to evaluate data in an ongoing fashion to select and optimize 
dose levels and dosing frequencies. Data from Period 1 (SAD) have been reviewed by the DEC 
and SMC in accordance with Section 4.4.1 and Section 4.4.2, respectively, and recommendations 
were made regarding the number of cohorts, number of patients per cohort, and dose levels for 
Period 1 and P2C1.   
In Period 1, the DEC/SMC have recommended dose escalation up to 90 mg. Initially, each 
cohort included 6 patients; however, due to variability in mHTT among patients, in 
September 2022, the DEC/SMC further recommended to expand each of the 3 single-dose 
cohorts to the cohort sizes listed below. Optional follow-up visits (up to 24 weeks postdose) were 
also added to provide the opportunity to obtain additional plasma and follow-up imaging samples 
prior to participation in Period 2. These additional data will be used to optimize the dose level:  
• P1C1: 30 mg (n = 18; 2:1 active:placebo) 
• P1C2: 60 mg (n = 18; 2:1 active:placebo) 
• P1C3: 90 mg (n = 12; 2:1 active:placebo) 
As of 07 December 2022, after review of 17-week repeat-dose GLP toxicity study data in 
cynomolgus monkeys in addition to the most recent clinical data cut (21 November 2021), the 
DEC/SMC recommended initiation of P2C1 with 30 mg administered Q8W through Week 16. 


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Subsequent dose levels, frequencies, number of cohorts, and number of patients per cohort will 
be determined based on DEC/SMC review of data from prior cohort(s), as described in 
Section 4.4.1.3, but will not exceed 90 mg administered Q8W.  
3 STUDY OBJECTIVES   
Primary Objective: 
• To evaluate the safety and tolerability of WVE-003 in patients with HD 
Secondary Objectives: 
• To characterize the PK of WVE-003 in plasma  
• To characterize the concentration of WVE-003 in CSF  
Exploratory Objectives: 
• To evaluate the PD effect of WVE-003 on the levels of mHTT protein in CSF 
• To evaluate the effect of WVE-003 on clinical measures of disease including the Unified 
Huntington’s Disease Rating Scale (UHDRS) and Short Problem Behaviors Assessment 
(PBA-s) 
• To evaluate the PD effects of WVE-003 on relevant biomarkers in CSF, plasma, and 
peripheral blood mononuclear cells (PBMCs) (e.g., levels of wtHTT protein, total huntingtin 
[tHTT] protein in CSF, and neurofilament light [NfL] in CSF and plasma) 
• To evaluate changes from baseline in magnetic resonance imaging (MRI) of the brain 
4 STUDY DESIGN  
4.1 
Study Design Overview 
This is a Phase 1b/2a multicenter, randomized, double-blind, placebo-controlled study to 
evaluate the safety, tolerability, PK, and PD of WVE-003 in adult patients with early-manifest 
HD who carry a targeted SNP rs362273 (SNP3).  
To participate in the study, patients must undergo prescreening to confirm they are heterozygous 
for SNP3 with the A variant on the same allele as the CAG triplet expansion. Prescreening can 
happen any time before Screening. The prescreening testing process to confirm the presence of 
SNP3 is expected to take up to 6 weeks. If patients meet these criteria, they will continue to the 
Screening visit. The prescreening assessment will have a separate informed consent form (ICF).  
The study will include 2 distinct periods: Period 1 to evaluate SAD cohorts and Period 2 to 
evaluate MAD cohorts of WVE-003. Patients may participate in Period 1 (SAD) and Period 2 


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(MAD) or Period 2 (MAD) only. All patients enrolled in Period 1 cohorts will have the 
opportunity to receive multiple doses in Period 2.  
Cohorts in both Period 1 and Period 2 will be enrolled and dosed in a sequential manner. 
Subsequent SAD or MAD cohorts will not initiate until the requirements for dose escalation are 
met (Section 4.4.1.1). This study will utilize both a DEC and a SMC. The DEC will be 
responsible for making recommendations regarding dose escalation in Period 1, initiation of 
multiple dosing in Period 2, and subsequent dose escalation in Period 2. Recommendations made 
by the DEC will be reviewed by the independent SMC. Details regarding DEC and SMC reviews 
to determine dose escalation for subsequent cohorts in both Period 1 and Period 2 are provided in 
Section 4.4.1. Treatment-emergent adverse events (TEAEs) that meet the Stopping Criteria will 
be reviewed by the unblinded SMC (Section 4.4.3.1). In addition, the SMC will review 
unblinded, aggregate safety data (Section 4.4.2).  
WVE-003 will be administered intrathecally in a volume of 20 mL of aCSF.  
A schematic of the overall study design and timing is provided in Figure 1. 
Of note, specific instructions regarding Coronavirus Disease 2019 (COVID-19) considerations 
are provided in Section 4.4.5. 


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Figure 1 
Schematic of Study Design  
 
 
 
Abbreviations: DEC = Dose Escalation Committee; MAD = multiple ascending dose; PxCx = Period x Cohort x; Q8W = every 8 weeks; SAD = single ascending 
dose; SMC = Safety Monitoring Committee; TBD = to be determined. 


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a 
DEC/SMC review of data from P1C1 (n = 11; 30 mg), P1C2 (n = 6; 60 mg), and P1C3 (n = 6; 90 mg) (data cutoff 21 Nov 2022) in conjunction with 
17-week repeat-dose cynomolgus monkey study. 
Note: DEC recommendations will be reviewed by the SMC. 
Dose and cohort size may be modified following recommendations from the DEC and SMC. As of 07 December 2022, planned cohort sizes and dose levels in 
Period 1 are as follows: P1C1 (n = 18; 30 mg), P1C2 (n = 18; 60 mg), and P1C3 (n = 12; 90 mg). The planned cohort size and dose level for P2C1 is 
approximately n = 24; 30 mg Q8W. 
 
 
 


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4.1.1 
Prescreening Phase 
All patients must undergo a Prescreening visit to determine that they have heterozygosity at SNP 
rs362273 (SNP3) with the A variant only on the same allele as the CAG triplet expansion. 
Eligibility is determined by evaluation of a blood sample, as described in Section 8.1. A blood 
sample may be collected at the Prescreening visit. Alternately, a blood sample collected 
previously for another HD study being conducted by the Sponsor may be used to determine 
eligibility. Patients must sign a prescreening ICF prior to collection of the sample or evaluation 
of a previously collected sample. The testing process is expected to take up to 6 weeks. 
Prescreening can happen any time before Screening. Patients should not undergo any Screening 
assessments until it is confirmed that they are eligible based on these criteria. If patients meet 
these criteria, they will continue to the Screening Phase.  
4.1.2 
Screening Phase 
The Screening period is intended to allow determination of patient eligibility for the study. It will 
begin when the study informed consent is signed. The ability of the patient to understand the 
consent form will be documented in the study ICF.  
The Screening period will last up to 4 weeks. The required screening evaluations are outlined in 
the Schedule of Assessments (Section 4.2). Screening assessments can occur on multiple days, 
provided they are within the Screening period. The Investigator will determine whether patients 
meet the eligibility criteria and will collect the demographic and medical data permitting full 
characterization of the patient. Please refer to Section 4.4.5 regarding specific considerations as 
related to the COVID-19 pandemic. 
Although this study is in early manifest disease, and therefore significant cognitive decline is not 
anticipated, it is important to demonstrate that patients are capable of understanding the 
information provided in the informed consent, and this needs to be documented in the source 
documents. The screening questionnaire provides documentation of whether the Investigator 
assessed if the patient is able to provide responses to the following domains: mental capacity, 
patient's previous psychiatry history, and patient's current psychiatric care. 
Patients will be screened prior to Period 1 (Table 1). Alternately, new patients enrolled directly 
into Period 2 will be screened prior to dosing in Period 2 (Table 3). 
Patients who fail the screening may be rescreened, as appropriate, in consultation with the 
Medical Monitor and when approved by the Sponsor. If a patient is rescreened within 1 month of 
the screening window, the MRI does not need to be repeated. A record of patient screen failures 
will be maintained for patients who do not qualify for enrollment, including the reason for the 
failure. 
A study partner is not required to participate in this study. However, if a patient will be attending 
most clinical visits with a study partner, this person should be identified during the Screening 


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phase. This person may provide additional information on the PBA-s assessment throughout the 
study (Section 8.7.2). 
4.1.3 
Period 1 (Single-ascending-dose Period) 
4.1.3.1 
Period 1 Treatment 
Period 1 will evaluate SAD cohorts of WVE-003. Eligible patients will be randomly allocated to 
either active or placebo treatment at the Baseline Visit. Patients will receive a single IT 
treatment. The planned Period 1 dose cohorts were as follows. Dose and cohort sizes were 
modified following recommendations from the DEC and SMC (details provided in Section 2.3). 
• P1C1: 6 patients (2:1 active:placebo); 30 mg  
• P1C2: 6 patients (2:1 active:placebo)  
If the DEC or the Sponsor determines additional single-dose data are required prior to initiating 
Period 2, subsequent SAD cohorts may be conducted. 
Within 1 week prior to performing the lumbar puncture, 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. Other predose assessments may also be performed up to 1 week prior to dosing as 
specifically listed in Table 1, including UHDRS, PBA-s, and weight. 
The first 2 patients (1:1 active:placebo) in Period 1 will be dosed and observed for 2 days in the 
clinic. If neither of these sentinel patients experiences a serious adverse event (SAE) during that 
period and the Single Dose Stopping Criteria (Section 4.4.3.1) are not met, the remaining 
patients will be dosed sequentially. If either of these events occur, the safety data will be 
reviewed by the SMC to determine the next steps (Section 4.4.2). Subsequent patients will be 
observed in the clinic for 1 day after dosing. Immediately after study drug administration, all 
patients should be ambulatory and active for approximately 30 minutes postdose. The 
Investigator should note any weakness or fatigue during this period. Formal physical 
examinations targeting the neurological system will be performed postdose at the time points 
specified in Table 1. 
The SAD cohorts will be conducted in a sequential manner. Subsequent SAD cohorts will not 
initiate until the criteria for dose escalation are met (Section 4.4.1.1). 
4.1.3.2 
Period 1 Follow-up 
All patients are required to complete follow-up assessments, including evaluations of safety, PD, 
PK, clinical effects, and MRI (Table 1). Patients will be followed up for a minimum of 12 weeks 
and up to 24 weeks postdose. Any postdose SAEs will be monitored until resolution. 
Prior to being enrolled into Period 2, patients will continue to attend monthly follow-up visits 
through Week 24. After Period 2 initiation (Section 4.1.4), patients can proceed to multiple 


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dosing in Period 2 if the Period 1 Week 12/Day 85 visit has been completed. All patients must 
complete the Period 1 Week 12/Day 85 visit to ensure a sufficient washout of study drug prior to 
beginning treatment in Period 2 (multiple-dose period).  
Visits on Weeks 16, 20, and 24 only need to be completed if the multiple-dose portion (Period 2) 
of the study has not initiated by the time the patient has reached Week 12/Day 85. At any point 
after Week 12/Day 85, the patient may roll over to Period 2 once initiated.  
Any patient who completed Week 12/Day 85 may be asked to return for the next applicable 
Period 1 visit according to their number of days postdose. If a patient is past Week 24/Day 169, 
they may be asked to return for the assessments outlined on the Week 24/Day 169 visit.   
Patients do not need to complete the visits on Weeks 16, 20, or 24 to be eligible for participation 
in Period 2. 
4.1.4 
Period 2 (Multiple-ascending-dose Period) 
Period 2 will not be initiated until this Substantial Amendment to the IMPD with the 
supportive nonclinical data is approved by the local regulatory authorities. Following this 
approval, the Sponsor intends to initiate Period 2. The Sponsor will communicate this 
approval (in writing) directly to the study sites. 
Based on data review of 17-week repeat-dose toxicity data in cynomolgus monkeys and clinical 
data from Period 1 (cutoff date 21 November 2022), the DEC/SMC recommended that Period 2 
can initiate at a dose level of 30 mg Q8W.   
4.1.4.1 
Period 2 Assessment of Continued Patient Eligibility 
Before initiation of Period 2, the Investigator should confirm patient eligibility to continue in the 
study (Section 4.2). If any clinically significant medical findings are observed that, in the 
judgment of the Investigator (and in consultation with the Sponsor), would make the patient 
unsuitable for continued participation in the study and/or completion of the study procedures, the 
patient may not be allowed to participate in Period 2. Applicable evaluations and tests from the 
last in-clinic visit in Period 1 may be used if the last in-clinic visit occurred within 4 weeks prior 
to the Confirm Eligibility visit for Period 2. Patients who are considered eligible and have 
completed at least through Period 1 Week 12/Day 85 may participate in Period 2. New patients 
will be screened for eligibility. 
4.1.4.2 
Period 2 Treatment Assignment 
Patients in P2C1 will receive 30 mg WVE-003 or placebo administered Q8W. Approximately 
24 patients will be enrolled in P2C1. Dose levels and cohort sizes for Period 2 subsequent 
cohorts will be determined by the DEC/SMC, based on previous Period 2 cohort data. Doses will 
be administered no more often than Q8W through Week 16 (maximum of 3 doses). The 
maximum dose in Period 2 is not to exceed 90 mg. 


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All patients from Period 1 will have the opportunity to roll into Period 2 and will receive up to 
3 additional doses of WVE-003 or placebo. Patients will not be re-randomized and will continue 
to receive active drug or placebo based on Period 1 treatment assignment. Patients will roll into 
the current Period 2 cohort, irrespective of Period 1 dose level. 
Patients may be replaced in accordance with the requirements for dose escalation. Future 
DEC/SMC recommendations may include the addition of new Period 2 patients. All new patients 
in Period 2 will receive up to 3 doses of WVE-003 administered no more often than Q8W.  
4.1.4.3 
Period 2 Treatment 
Within 1 week prior to performing any lumbar puncture, 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. Other predose assessments may also be performed up to 1 week prior to dosing as 
specifically listed in Table 3 including UHDRS, PBA-s, and weight. 
The Period 2 MAD cohorts will be conducted in a sequential manner. Subsequent multiple-dose 
cohorts will not initiate until the criteria for dose escalation are met (Section 4.4.1.3). 
Immediately after study drug administration in any cohort, all patients should be ambulatory and 
active for approximately 30 minutes postdose on all dosing days. The Investigator should note 
any weakness or fatigue during this period. Formal physical examinations targeting the 
neurological system will be performed postdose at the time points specified in Table 3. 
Patients will attend clinic visits Q4W for assessments of safety, PK, and PD. Patients in P2C1 
will receive doses on Week 0, Week 8, and Week 16. Pending DEC/SMC recommendation, 
subsequent cohorts may receive doses Q8W or less frequently (e.g., on Week 0 and Week 12).  
4.1.4.4 
Period 2 Follow-up  
All patients are required to complete follow-up assessments, including evaluations of safety, PD, 
PK, clinical effects, and MRI. Patients will be followed up for a minimum of 12 weeks after the 
last dose. Any postdose SAEs will be monitored until resolution.  
4.1.5 
Early Termination Visit 
If a patient withdraws from the study early, the patient should complete an early termination 
visit. Refer to Section 5.3 for information on early withdrawal from study drug or from the study.  
4.2 
Schedule of Assessments 
The schedule of assessments for Period 1 is presented in Table 1. Detailed time points for select 
assessments in Period 1 are provided in Table 2. 
The schedule of all assessments for Period 2 is presented in Table 3. Detailed time points for 
select assessments in Period 2 are provided in Table 4. 


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Of note, specific instructions regarding COVID-19 considerations, are provided in Section 4.4.5.


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Table 1 
Schedule of Assessments (Period 1) 
 
Pre-
screen-
inga 
Screeningb 
Double-blind Treatment  
(Single Dose) 
Sentinel 
Patient 
Follow-
up 
Required Follow-up 
Additional Follow-up 
Visits 
ET 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10* 
11* 
12* 
Week 
 
-4 to 0 
0 
0 
0 
2 
4 
8 
12 
16 
20 
24 
Study Day 
(Visit Window, if 
applicable) 
Event/Assessment 
Day -28 to 
-1 
Baseline  
(Day -6 to  
Day 1)c 
Dosing 
(Day 1) 
D2 
(24 ± 4 h 
postdose) 
D3 
(48 ± 4 h 
postdose) 
D15  
(±2) 
D29 
(±2) 
D57  
(±3) 
D85  
(±5) 
D113 
(±5) 
D141 
(±5) 
D169 
(±5) 
Prescreening patient 
informed consent form 
(ICF) signed 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Patient Study ICF 
Signed 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Screening Questionnaire  
 
X 
 
 
 
 
 
 
 
 
 
 
 
Blood sample for 
Prescreening assays 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
criteria 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Medical history and 
demographics 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Prior and concomitant 
medications 
 
X 
Xc,k 
Xk 
Xk 
X 
X 
X 
X 
X 
X 
X 
X 
Hepatitis (HBsAg, HCV) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
C-SSRS 
“Baseline/Screening”d 
 
X 
 
 
 
 
 
 
 
 
 
 
 


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Pre-
screen-
inga 
Screeningb 
Double-blind Treatment  
(Single Dose) 
Sentinel 
Patient 
Follow-
up 
Required Follow-up 
Additional Follow-up 
Visits 
ET 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10* 
11* 
12* 
Week 
 
-4 to 0 
0 
0 
0 
2 
4 
8 
12 
16 
20 
24 
Study Day 
(Visit Window, if 
applicable) 
Event/Assessment 
Day -28 to 
-1 
Baseline  
(Day -6 to  
Day 1)c 
Dosing 
(Day 1) 
D2 
(24 ± 4 h 
postdose) 
D3 
(48 ± 4 h 
postdose) 
D15  
(±2) 
D29 
(±2) 
D57  
(±3) 
D85  
(±5) 
D113 
(±5) 
D141 
(±5) 
D169 
(±5) 
C-SSRS “Since Last 
Visit”d 
 
 
Xc 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
UHDRSd 
 
X 
X 
 
 
 
 
 
X 
 
 
X 
X 
PBA-sd 
 
X 
X 
 
 
 
 
 
X 
 
 
X 
X 
Weight 
 
X 
X 
 
 
 
 
 
X 
 
 
X 
X 
Height 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Physical examinatione 
 
X 
Xc 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
Targeted postdose 
physical examination of 
motor effectsf 
 
 
Xc 
 
 
 
 
 
 
 
 
 
 
Blood pressure and 
pulseg 
 
X 
Xc 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Temperature 
 
X 
Xc 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urine pregnancy testh 
 
 
Xc 
 
 
 
 
 
 
 
 
X 
X 
Serum pregnancy testh 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Drug screen 
 
X 
 
 
 
 
 
 
 
 
 
 
 


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Pre-
screen-
inga 
Screeningb 
Double-blind Treatment  
(Single Dose) 
Sentinel 
Patient 
Follow-
up 
Required Follow-up 
Additional Follow-up 
Visits 
ET 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10* 
11* 
12* 
Week 
 
-4 to 0 
0 
0 
0 
2 
4 
8 
12 
16 
20 
24 
Study Day 
(Visit Window, if 
applicable) 
Event/Assessment 
Day -28 to 
-1 
Baseline  
(Day -6 to  
Day 1)c 
Dosing 
(Day 1) 
D2 
(24 ± 4 h 
postdose) 
D3 
(48 ± 4 h 
postdose) 
D15  
(±2) 
D29 
(±2) 
D57  
(±3) 
D85  
(±5) 
D113 
(±5) 
D141 
(±5) 
D169 
(±5) 
Adverse event 
monitoring 
 
X 
Xc,k 
Xk 
Xk 
X 
X 
X 
X 
X 
X 
X 
X 
Pre-LP PT and plateleti 
 
 
X 
 
 
X 
X 
X 
X 
 
 
 
Xl 
12-Lead ECG 
 
Refer to Table 2 
Clinical laboratory tests 
 
Refer to Table 2 
Blood sample for PK 
and PD 
 
Refer to Table 2 
Urine sample for PK 
 
Refer to Table 2 
Serum sample for 
immunogenicity 
 
Refer to Table 2 
CSF sample for safety, 
drug concentration, and 
PD 
 
Refer to Table 2 
PBMC sample for 
biomarker analyses 
 
Refer to Table 2 
3T MRI of the brain 
(without contrast) 
 
X 
 
 
 
 
 
 
 
 
 
X 
X 


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Pre-
screen-
inga 
Screeningb 
Double-blind Treatment  
(Single Dose) 
Sentinel 
Patient 
Follow-
up 
Required Follow-up 
Additional Follow-up 
Visits 
ET 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10* 
11* 
12* 
Week 
 
-4 to 0 
0 
0 
0 
2 
4 
8 
12 
16 
20 
24 
Study Day 
(Visit Window, if 
applicable) 
Event/Assessment 
Day -28 to 
-1 
Baseline  
(Day -6 to  
Day 1)c 
Dosing 
(Day 1) 
D2 
(24 ± 4 h 
postdose) 
D3 
(48 ± 4 h 
postdose) 
D15  
(±2) 
D29 
(±2) 
D57  
(±3) 
D85  
(±5) 
D113 
(±5) 
D141 
(±5) 
D169 
(±5) 
Study drug 
administration via IT 
injectionj 
 
 
Xc 
 
 
 
 
 
 
 
 
 
 
Abbreviations: 3T = 3 Tesla; A = adenine; AE = adverse event; CAG = cytosine-adenine-guanine; CSF = cerebrospinal fluid; C-SSRS = Columbia-Suicide Severity Rating Scale; D = day; 
ECG = electrocardiogram; EOS = end of study; ET = early termination; h = hour; HBsAg = hepatitis B surface antigen; HCV = hepatitis C virus; ICF = informed consent form; IT = intrathecal; LP = 
lumbar puncture; MRI = magnetic resonance imaging; PBA-s = Short Problem Behaviors Assessment; PBMC = peripheral blood mononuclear cell; PD = pharmacodynamic(s); PK = 
pharmacokinetic(s); PT = prothrombin time; SNP = single nucleotide polymorphism; SNP3 = SNP rs362273; UHDRS = Unified Huntington’s Disease Rating Scale; W = week.  
* Visits on W16, W20, and/or W24 only need to be completed if the multiple-dose portion (Period 2) of the study has not initiated by the time the patient has reached W12/D85. At any point after 
W12/D85, the patient may roll over to Period 2 once initiated. Any patient who completes W12/D85 may be asked to return for the next applicable visit according to their number of days postdose. If 
a patient is past W24/D169, they may be asked to return for the assessments outlined on the W24/D169 visit.   
a 
Prescreening must be performed to confirm heterozygosity at SNP3 with the A variant only on the same allele as the CAG triplet expansion. Prescreening can happen any time before Screening. It is 
anticipated that it will take up to 6 weeks to process the results of this testing. 
b 
Screening assessments can occur on multiple days, provided they are within the 4-week Screening period.   
c 
Noted predose/baseline procedures must be performed within 24 hours predose. All others can be performed up to 1 week prior to dosing. Postdose procedures should be performed as described for 
each assessment. 
d 
The UHDRS, PBA-s, and C-SSRS should be completed prior to any other assessments. 
e 
Physical examination includes (at a minimum) the head, eyes, ears, nose, and throat, as well as the respiratory, cardiovascular, gastrointestinal, musculoskeletal, psychiatric, and neurologic systems. 
Predose physical examination should be done on Day 1 prior to dosing.  
f 
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 hours postdose (±15 minutes) on Day 1. 
g 
Blood pressure (systolic and diastolic) and pulse will be measured ≤60 minutes predose and 4 hours (±15 minutes) postdose on Day 1 and once at all other noted visits. Patient must rest quietly for 
≥3 minutes prior to measuring. 
h 
Negative serum pregnancy test will be documented at Screening for female patients. Negative urine pregnancy test will be documented predose for female patients on Day 1. 
i 
Blood sample will be tested locally for platelet count and prothrombin time pre-LP to confirm safe to proceed with the lumbar puncture. 
j 
Immediately after study drug administration, patients should be active for approximately 30 minutes postdose.  
k 
All patients will remain in the clinic and have AEs and concomitant medications recorded through 1 day postdose. In addition, 2 sentinel patients will remain in the clinic and have AEs and 
concomitant medications recorded throughout the 2-day postdose period.  


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l 
This assessment will be performed only if optional lumbar puncture is performed at ET.  
 
 
 
 


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Table 2 
Detailed Time Points for Selected Assessments (Period 1) 
Assessments 
Screening 
D1 
D2 
Sentinel 
Patient 
Fol/up 
D3 
W2 
(D15) 
W4 
(D29) 
W8 
(D57) 
W12  
(D85) 
W16 
(D113), 
W20 
(D141)*  
W24 
(D169)* 
ET 
Pre-
dose 
Postdose 
30 m 
1 h 
2 h 
4 h 
6 h 
0 to 
4 h  
4 to 
8 h  
8 to 
24 h 
24 h 
48 h 
Window (±) 
4 h 
5 m 
15 m 
15 m 
30 m 
30 m 
2 h 
2 h 
2 h 
2 h 
4 h 
2 d 
2 d 
3 d 
5 d 
5 d 
5 d 
 
CSF samplea 
 
X 
 
 
 
 
 
 
 
 
 
 
X  
X 
X 
X 
 
 
Xb 
Plasma PD 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
Plasma PK  
 
X 
X 
X 
X 
X 
X 
 
 
 
X 
 
X 
X 
X 
X 
 
 
X 
Urine PK 
 
 
 
 
 
 
 
X 
X 
X 
 
 
 
 
 
 
 
 
 
PBMC sample 
for biomarker 
analyses 
 
X 
 
 
 
 
 
 
 
 
X 
 
X 
X 
X 
X 
 
X 
X 
ECGc 
X 
X 
 
X 
X 
X 
 
 
 
 
X 
 
 
 
 
 
X 
X 
X 
Serum sample 
for 
Immunogenicity 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
Clinical 
laboratory tests 
(full panel)d 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
X 
Clinical 
laboratory tests 
(CBC, CRP, 
complement, 
and fibrinogen) 
 
 
 
X 
 
X 
 
 
 
 
X 
X 
 
 
 
 
 
 
 
Abbreviations: CBC = complete blood count; CRP = C-reactive protein; CSF = cerebrospinal fluid; D = day; ECG = electrocardiogram; ET = early termination; h = hour; m = minute; 
PBMC = peripheral blood mononuclear cell; PD = pharmacodynamic(s); PK = pharmacokinetic(s); W = week. 
*Visits on W16, W20, and/or W24 only need to be completed if the multiple-dose portion (Period 2) of the study has not initiated by the time the patient has reached W12/D85. At any point after 
W12/D85, the patient may roll over to Period 2 once initiated. Any patient who completes W12/D85 may be asked to return for the next applicable visit according to their number of days postdose. If 
a patient is past W24/D169, they may be asked to return for the assessments outlined on the W24/D169 visit.   
a On Day 1, CSF sample will be collected approximately 15 minutes prior to study drug administration. At all noted time points, approximately 20 mL of CSF total should be collected. CSF samples 
must be tested locally for safety for the following parameters: total protein, glucose, and cell counts (white blood cell counts with differential) on all noted visits.  
b This lumbar puncture is optional for patients who terminate early. 


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c Electrocardiogram recordings will be obtained in triplicate in the supine position after the patient has rested comfortably for ≥10 minutes. ECGs should be performed in triplicate. At time points when 
plasma PK is also being collected, the ECG should be performed first, and PK should be collected within 30 minutes after (and within the applicable postdose window). 
d Parameters to be assessed are detailed in Table 6. Clinical laboratory safety baseline assessments will be performed up to 1 week prior to dosing. Note that these assessments also include CBC, CRP, 
complement, and fibrinogen. 
 
 
 


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Table 3 
Schedule of Assessments (Period 2)  
Visit 
New Patients Only 
Rollover 
Patients 
Double-blind Treatmentc  
(Repeat Dose) 
Follow-up 
ET 
Pre-
screen-
inga 
Screen-
ingb 
Confirm 
Eligibility 
3 
New 
Patients 
Only 
 
5 
 
6 
 
7 
 
8 
 
 
 
9 
 
10 
 
11 (EOS) 
1 
2 
2 
4 
Week 
 
-4 to 0 
-4 to 0 
0 
4  
8 
12 
16 
20 
24 
28 
Study Day 
(Visit Window, if 
applicable) 
Event/Assessment 
Day  
-28 to -1 
Day -28 
to -1 
Baseline  
(Day -6 
to  
Day 1) 
Dosing 
(Day 1) 
D2 
(24 ± 4 h 
postdose) 
D29 (±3) 
D57 
(±3) 
D85 
(±3) 
D113 
(±3) 
 
 
 
D141 
(±3) 
D169  
(±3) 
D197 
(±5) 
Prescreening patient 
informed consent 
form (ICF) signed 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Screening 
Questionnaire 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Patient Study ICF 
Signed 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Blood sample for 
Prescreening assays 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
criteria 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Medical history and 
demographics 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Prior and concomitant 
medications 
 
X 
 
Xc,l 
Xl 
Xc 
Xc 
Xc 
Xc 
X 
X 
X 
X 
Hepatitis (HBsAg, 
HCV) 
 
X 
 
 
 
 
 
 
 
 
 
 
 


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Visit 
New Patients Only 
Rollover 
Patients 
Double-blind Treatmentc  
(Repeat Dose) 
Follow-up 
ET 
Pre-
screen-
inga 
Screen-
ingb 
Confirm 
Eligibility 
3 
New 
Patients 
Only 
 
5 
 
6 
 
7 
 
8 
 
 
 
9 
 
10 
 
11 (EOS) 
1 
2 
2 
4 
Week 
 
-4 to 0 
-4 to 0 
0 
4  
8 
12 
16 
20 
24 
28 
Study Day 
(Visit Window, if 
applicable) 
Event/Assessment 
Day  
-28 to -1 
Day -28 
to -1 
Baseline  
(Day -6 
to  
Day 1) 
Dosing 
(Day 1) 
D2 
(24 ± 4 h 
postdose) 
D29 (±3) 
D57 
(±3) 
D85 
(±3) 
D113 
(±3) 
 
 
 
D141 
(±3) 
D169  
(±3) 
D197 
(±5) 
C-SSRS 
“Baseline/Screening”d 
 
X 
 
 
 
 
 
 
 
 
 
 
 
C-SSRS “Since Last 
Visit”d 
 
 
Xo 
Xc 
X 
Xc 
Xc 
Xc 
Xc 
X 
X 
X 
X 
UHDRSd 
 
X 
Xo 
X 
 
 
 
 
X 
 
X 
 
X 
PBA-sd 
 
X 
Xo 
X 
 
 
 
 
X 
 
X 
 
X 
Weighte 
 
X 
 
X 
 
X 
X 
X 
X 
 
X 
 
X 
Height 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Physical examinationf 
 
X 
X 
Xc 
X 
Xc 
Xc 
Xc 
Xc 
X 
X 
X 
X 
Targeted postdose 
physical examination 
of motor effectsg 
 
 
 
Xc 
 
 
Dosing visits only 
 
 
 
 
Blood pressure and 
pulseh 
 
X 
X 
Xc 
X 
Xc 
Xc 
Xc 
Xc 
X 
X 
X 
X 
Temperaturee 
 
X 
X 
Xc 
X 
Xc 
Xc 
Xc 
Xc 
X 
X 
X 
X 
Urine pregnancy testi 
 
 
 
Xc 
 
Xc 
Xc 
Xc 
Xc 
 
 
 
X 
Serum pregnancy testi 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
Drug screen 
 
X 
X 
 
 
 
 
 
 
 
 
 
 


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Visit 
New Patients Only 
Rollover 
Patients 
Double-blind Treatmentc  
(Repeat Dose) 
Follow-up 
ET 
Pre-
screen-
inga 
Screen-
ingb 
Confirm 
Eligibility 
3 
New 
Patients 
Only 
 
5 
 
6 
 
7 
 
8 
 
 
 
9 
 
10 
 
11 (EOS) 
1 
2 
2 
4 
Week 
 
-4 to 0 
-4 to 0 
0 
4  
8 
12 
16 
20 
24 
28 
Study Day 
(Visit Window, if 
applicable) 
Event/Assessment 
Day  
-28 to -1 
Day -28 
to -1 
Baseline  
(Day -6 
to  
Day 1) 
Dosing 
(Day 1) 
D2 
(24 ± 4 h 
postdose) 
D29 (±3) 
D57 
(±3) 
D85 
(±3) 
D113 
(±3) 
 
 
 
D141 
(±3) 
D169  
(±3) 
D197 
(±5) 
Adverse event 
monitoring 
 
X 
X 
Xc,l 
Xl 
Xc 
Xc 
Xc 
Xc 
X 
X 
X 
X 
Pre-LP PT and 
plateletj 
 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
Xm 
12-lead ECG 
X 
X 
 
Xp 
 
X 
X 
X 
X 
X 
 
 
X 
Clinical laboratory 
tests  
X 
X 
X 
Xp 
Xp 
Xp 
Xp 
Xp 
Xp 
Xp 
Xp 
Xp 
Xp 
Blood sample for PK 
and PD 
 
 
 
Xp 
Xp 
Xp 
Xp 
Xp 
Xp 
Xp 
Xp 
Xp 
Xp 
Serum sample for 
immunogenicity 
 
 
 
Xp 
 
Xp 
Xp 
Xp 
Xp 
Xp 
Xp 
Xp 
Xp 
CSF sample for 
safety, drug 
concentration, and PD 
 
 
 
Xp 
 
Xp 
Xp 
Xp 
Xp 
Xp 
Xp 
Xp 
Xp 
PBMC sample for 
biomarker analyses 
 
 
 
Xp 
Xp 
Xp 
Xp 
Xp 
Xp 
 
 
Xp 
Xp 
3T MRI of the brain 
(without contrast) 
 
X 
 
Xn 
 
 
 
 
 
 
X 
 
 


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Visit 
New Patients Only 
Rollover 
Patients 
Double-blind Treatmentc  
(Repeat Dose) 
Follow-up 
ET 
Pre-
screen-
inga 
Screen-
ingb 
Confirm 
Eligibility 
3 
New 
Patients 
Only 
 
5 
 
6 
 
7 
 
8 
 
 
 
9 
 
10 
 
11 (EOS) 
1 
2 
2 
4 
Week 
 
-4 to 0 
-4 to 0 
0 
4  
8 
12 
16 
20 
24 
28 
Study Day 
(Visit Window, if 
applicable) 
Event/Assessment 
Day  
-28 to -1 
Day -28 
to -1 
Baseline  
(Day -6 
to  
Day 1) 
Dosing 
(Day 1) 
D2 
(24 ± 4 h 
postdose) 
D29 (±3) 
D57 
(±3) 
D85 
(±3) 
D113 
(±3) 
 
 
 
D141 
(±3) 
D169  
(±3) 
D197 
(±5) 
Study drug 
administration via 
IT injectionk 
 
 
 
Xc 
 
 
Dosing visits onlyc 
 
 
 
 
Study completion 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Abbreviations: 3T = 3 Tesla; A = adenine; AE = adverse event; CAG = cytosine-adenine-guanine; CSF = cerebrospinal fluid; C-SSRS = Columbia-Suicide Severity Rating Scale; D = day; 
ECG = electrocardiogram; EOS = end of study; ET = early termination; h = hour; HBsAg = hepatitis B surface antigen; HCV = hepatitis C virus; ICF = informed consent form; IT = intrathecal; LP = 
lumbar puncture; MRI = magnetic resonance imaging; PBA-s = Short Problem Behaviors Assessment; PBMC = peripheral blood mononuclear cell; PD = pharmacodynamics; PK = pharmacokinetics; 
PT = prothrombin time; SNP = single nucleotide polymorphism; SNP3 = SNP rs362273; UHDRS = Unified Huntington’s Disease Rating Scale.  
a 
Prescreening must be performed to confirm heterozygosity at SNP3 with the A variant only on the same allele as the CAG triplet expansion. Prescreening can happen any time before Screening. It is 
anticipated that it will take up to 6 weeks to process the results of this testing. 
b 
Screening assessments can occur on multiple days, provided they are within the 4-week Screening period.   
c 
Noted assessment must be performed within 24 hours predose. All others can be performed up to 1 week prior to dosing. Postdose procedures should be performed as described for each assessment. 
d 
The UHDRS, PBA-s, and C-SSRS should be completed prior to any other assessments. 
e 
Weight and temperature will be collected predose on dosing days and once at all other noted time points. 
f 
Physical examination includes (at a minimum) the head, eyes, ears, nose, and throat, as well as the respiratory, cardiovascular, gastrointestinal, musculoskeletal, psychiatric, and neurologic systems. 
Predose physical examination should be done on the day of dosing.  
g 
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 hours postdose (±15 minutes) on all dosing days. 
h 
Blood pressure (systolic and diastolic) and pulse will be measured ≤60 minutes predose and 4 hours (±15 minutes) postdose on dosing days and once at all other noted visits. Patient must rest quietly 
for ≥3 minutes prior to measuring. 
i 
Negative serum pregnancy test will be documented at Screening for new female patients in Period 2. Negative urine pregnancy test will be documented predose for female patients on dosing days. 
j 
Blood sample will be tested locally for platelet count and prothrombin time up to 1 week prior to any LP to confirm safe to proceed with the lumbar puncture. 
k 
Immediately after study drug administration, patients who are able should be active for approximately 30 minutes postdose. If the DEC decides to reduce dose frequency or number of doses 
(Section 4.4.1.3), patients will complete all study assessments at the noted visits, but may not receive study drug.  
l All patients will remain in the clinic and have AEs and concomitant medications recorded through 1 day postdose.  


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m This assessment will be performed only if optional lumbar puncture is performed at ET.  
n This MRI should be performed for rollover patients only. If the Period 1 Week 24/Day 169 visit was conducted <4 weeks prior to the Period 2 Day 1 visit, the MRI does not need to be repeated. 
o Assessments from the last in-clinic visit in Period 1 may be used if the last in-clinic visit occurred within 4 weeks prior to the Confirm Eligibility visit for Period 2. 
p Reference Table 4 for details regarding assessments and time points.  
 
 
 
 


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Table 4 
Detailed Time Points for Selected Assessments (Period 2) 
Assessment 
New 
Patients 
Only 
Roll-over 
Patients 
D1 
New 
Patients 
Only 
W4 
(D29) 
W8 (D57) 
W12(D85) and W16 (D113) 
W20 
(D141) 
W24 
(D169 
W28  
(D197) 
ET 
Screen-
ing 
Confirm 
Eligibility  
D2 
Pre 
dose 
Postdose 
 
Pre-dose 
Postdose 
(Dosing 
Visit Only) 
Pre-
dose 
Postdose  
(Dosing Visit Only) 
 
 
4h 
30 m 1 h 2 h 4 h 6 h 
8 to 
24 
h 
24 h 
 
4 h 
2 hr 
4 h 
30 m 
1 h 
2 h 4 h 6 h 
 
 
 
 
Window (±) 
5 m 
15 
m 
15 
m 
30 
m 30 m 2h 
2h 
1 h 
5 m 
15 m 15 m 
30 
m 30 m 
3 d 
3 d 
3 d 
CSF samplea 
 
 
X 
 
 
 
 
 
 
 
X 
X 
 
X 
 
 
 
 
 
X  
X  
X 
Xb 
Plasma PD 
 
 
X 
 
 
 
 
 
 
 
X 
X 
 
X 
 
 
 
 
 
X 
X 
X 
X 
Plasma PK 
 
 
X 
X 
X 
X 
X 
X 
 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PBMC sample 
for biomarker 
analyses 
 
 
X 
 
 
 
 
 
 
X 
X 
X 
 
X 
 
 
 
 
 
 
 
X 
X 
ECGc 
Xe 
 
X 
 
X 
X 
X 
 
 
X 
 
 
 
X 
 
X 
 
 
 
X 
 
 
X 
Serum sample 
for 
Immunogenicity 
 
 
X 
 
 
 
 
 
 
 
X 
X 
 
X 
 
 
 
 
 
X 
X 
X 
X 
Clinical 
laboratory tests 
(full panel)d 
Xe 
Xe 
X 
 
 
 
 
 
 
 
X 
X 
 
X 
 
 
 
 
 
X 
X 
X 
X 
Clinical 
laboratory tests 
(CBC, CRP, 
complement, 
fibrinogen) 
 
 
 
 
X 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abbreviations: CBC = complete blood count; CRP = C-reactive protein; CSF = cerebrospinal fluid; D = day; ECG = electrocardiogram; ET = early termination; h = hour; m = minute; 
PBMC = peripheral blood mononuclear cell; PD = pharmacodynamic(s); PK = pharmacokinetic; W = week. 
a Predose on all dosing days, CSF sample will be collected approximately 15 minutes prior to study drug administration. At all noted time points, approximately 20 mL of CSF total should be collected. 
CSF samples must be tested locally for safety for the following parameters: total protein, glucose, and cell counts (white blood cell counts with differential) on all noted visits.  
b This lumbar puncture is optional for patients who terminate early. 


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c Electrocardiogram recordings will be obtained in the supine position after the patient has rested comfortably for ≥10 minutes. At time points when plasma PK is also being collected, the ECG should 
be performed first, and PK should be collected within 30 minutes after (and within the applicable postdose window). 
d Parameters to be assessed are detailed in Table 6. Clinical laboratory safety assessments will be performed up to 1 week prior to dosing on all dosing days.  Note that these assessments also include 
CBC, CRP, complement, and fibrinogen. 
e Assessments from the last in-clinic visit in Period 1 may be used if the last in-clinic visit occurred within 4 weeks prior to the Confirm Eligibility visit for Period 2..


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4.3 
Study Endpoints 
Safety 
Adverse events, concomitant medications, physical examinations including detailed neurological 
examination, vital signs, weight, 12-lead electrocardiograms (ECGs), clinical laboratory 
evaluations (including clinical chemistry, hematology, and urinalysis), CSF safety evaluations, 
MRI of the brain, and Columbia-Suicide Severity Rating Scale (C-SSRS) 
Pharmacokinetics 
• Pharmacokinetic parameters of WVE-003 in plasma at predefined time points  
• Concentration of WVE-003 in CSF at predefined time points   
Pharmacodynamics 
• Change from baseline in the level of mHTT protein in CSF  
• Change from baseline in the level of tHTT protein in CSF  
• Change from baseline in the level of wtHTT protein in CSF  
• Change from baseline in the level of NfL in CSF  
• Change from baseline in the level of exploratory biomarkers in CSF, plasma, and/or 
PBMCs  
Clinical Effects 
• Change from baseline in the UHDRS Total Functional Capacity (TFC) 
• Change from baseline in UHDRS total motor score 
• Change from baseline in the UHDRS independence scale 
• Change from baseline in Symbol Digit Modalities Test (SDMT) 
• Change from baseline in Stroop word reading test 
• Change from baseline in the composite UHDRS 
• Change from baseline in the PBA-s 
• Changes from baseline in MRI of the brain 


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4.4 
Safety Considerations 
4.4.1 
Dose Escalation Committee Review 
The DEC will be responsible for making recommendations regarding dose escalation in Period 1, 
initiation of multiple dosing in Period 2, and subsequent dose escalation in Period 2. The DEC 
will review blinded data. All recommendations of this committee will be reviewed by the SMC, 
which makes the final recommendation.  
4.4.1.1 
Period 1 – Dose Escalation 
After all patients in a Period 1 cohort have received study drug and completed 2 weeks of 
postdose follow-up, the DEC will review the available blinded safety and PK data. The DEC will 
determine if it is safe to proceed with the next single-dose cohort. Based on data review, the 
DEC may decide to add additional cohorts or select alternate dose levels for any of the cohorts. 
Selected dose levels will not increase by >3-fold the previous dose level and will not exceed a 
maximum dose of 168 mg, unless addressed by a protocol amendment. Additionally, at the 
selected dose level, the mean AUC0-24h or mean Cmax should not exceed 81.6 μg*hr/mL and 19.5 
μg/mL, respectively. 
4.4.1.2 
Initiation of Period 2  
The DEC will review the available safety and PK data and decide if Period 2 (i.e., P2C1) can be 
initiated. Note that Period 2 will not be initiated until this Substantial Amendment to the 
IMPD with the supportive nonclinical data is approved by the local regulatory authorities. 
4.4.1.3 
Period 2 – Subsequent MAD Cohorts (P2C2 and P2C3) 
Once 6 patients in the current cohort have received at least 2 consecutive doses, the DEC will 
review the available blinded safety and PK data and determine if it is safe to proceed with the 
subsequent multiple-dose cohort. Based on data review, the DEC may decide to add additional 
cohorts, select alternate dose levels (including lower doses), reduce the number of doses or 
reduce the frequency of dose administration for any of the cohorts, or change the number of 
patients planned for a cohort. Selected dose levels will not increase by >3-fold the previous dose 
level and will not exceed 90 mg Q8W, the highest dose level evaluated in Period 1. Additionally, 
at the selected dose level, the mean AUC0-24h or mean Cmax should not exceed 81.6 µg*hr/mL or 
19.5 µg/mL, the respective exposures following 15 mg Q8W in monkeys. 
4.4.2 
Safety Monitoring Committee Review 
In addition to reviewing the DEC’s decisions, the SMC will review unblinded aggregate safety 
data periodically and on an ad hoc basis throughout the study. The SMC will review any SAEs 
that occur in sentinel patients in order to determine if the cohort should continue or if a lower 
dose should be selected. In addition, if TEAEs occur that meet the Stopping Criteria, the SMC 
will review the unblinded safety data and determine whether it is safe to proceed with the cohort 
or if a lower dose should be explored. 


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If the stopping criteria are met at any point in the study, enrollment and dosing will be suspended 
until the data are reviewed. Similarly, if an SAE occurs in the sentinel patients in a cohort, no 
additional patients will be dosed in that cohort until the safety data are reviewed. Details on 
communication of safety concerns are detailed in Section 4.4.4. 
4.4.3 
Stopping Criteria  
4.4.3.1 
Single Dose Stopping Criteria (Cohort Stopping Criteria) 
During Period 1, dosing of patients in a cohort will be suspended: 
• If a single patient experiences an SAE assessed as related to study drug; 
• If 2 patients experience a severe TEAE that is assessed as related to study drug; or 
• If 4 patients experience a non-serious moderate or severe TEAE within the Medical 
Dictionary for Regulatory Activities (MedDRA) High Level Group Term (HLGT) Spinal 
cord and nerve root disorders, assessed as related to study drug. 
Notification of dose suspension for a given cohort will be made in accordance with applicable 
regulations. If a determination is made to resume the study, information will be submitted to the 
regulatory authorities in accordance with local regulations (e.g., substantial amendment) prior to 
restarting treatment.   
4.4.3.2 
Period 2 Stopping Criteria 
During Period 2, either of the following will result in a dosing halt within the cohort and trigger 
assessment by the SMC to decide the safe dose level in Period 2: 
• If 2 patients in a cohort experience an SAE assessed as at least possibly related to study 
drug. 
• If 2 patients in a cohort experience a non-serious severe TEAE assessed as at least 
possibly related to study drug. 
In addition, dosing will be stopped in any ongoing higher dose cohorts if the stopping rule is met 
in a lower-dose Period 2 cohort. 
Notification of dose suspension for a given cohort will be made in accordance with applicable 
regulations. If a determination is made to resume the study, information will be submitted to the 
regulatory authorities in accordance with local regulations (e.g., substantial amendment) prior to 
restarting treatment.   
4.4.3.3 
Individual Stopping Criteria 
Dosing will be stopped for an individual patient at any time in the study if: 


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• A patient experiences a serious or intolerable adverse event (AE) that, in the 
Investigator’s opinion, requires study drug discontinuation. 
• A patient experiences a TEAE that is severe in intensity and related to administration of 
WVE-003 (except TEAEs associated with lumbar puncture). 
The patient will be followed up for safety per protocol. Per the Investigator’s judgement, the 
patient may be allowed to resume participation in the study if or when the event has resolved]. 
Dosing may be resumed for individual patients upon recovery from the severe event and if 
supported by the Investigator, based on their assessment of the benefit/risk balance for the 
patient. 
4.4.3.4 
Adverse Events That are Exempt from Stopping Criteria 
Intrathecal administration of drugs is known to result in untoward effects such as post-lumbar 
puncture headache, pain, etc.33,34 Given the common occurrence of such side effects following 
lumbar puncture, it is anticipated that patients may experience AEs temporal to the IT 
administration procedure that are not attributable to study drug33,34. Therefore, the AE terms 
listed in Table 5 will be exempted from the assessment of Stopping Criteria:   
Table 5 
Adverse Event Preferred Terms Exempted From Stopping Criteria 
Preferred Terms Exempt From Stopping Criteria 
Administration site bruise 
Instillation site bruise 
Catheter site bruise 
Post-lumbar puncture syndrome 
Infusion site bruising 
Post-procedural discomfort 
Infusion site discomfort 
Post-procedural contusion 
Infusion site pain 
Procedural headache 
Injection site bruising 
Procedural pain 
Injection site discomfort 
Traumatic lumbar puncture 
Injection site pain 
 
 
Abbreviations: AE = adverse event; MedDRA = Medical Dictionary for Regulatory Activities; PT = Preferred 
Term. 
Note: AEs exempted from the Stopping Criteria include the MedDRA PTs listed above and their associated 
verbatim terms. 
While these procedural events are exempt from Stopping Criteria review, they will be recorded 
as AEs as described in Section 9. In addition, as part of their ongoing review of unblinded safety 
data, the SMC will carefully review the above-referenced exempted AE terms to ensure there are 
no meaningful imbalances between treatment groups. 


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4.4.4 
Communication of Emergent Safety Concerns 
Enrollment to the study will be closely monitored by the Sponsor. If the stopping criteria are met 
at any point in the study, enrollment and dosing will be suspended until the data are reviewed by 
the SMC. Notification of dose suspension for a given cohort will be made in accordance with 
applicable regulations. If a determination is made to resume the study, information will be 
submitted to the regulatory authorities in accordance with local regulations (e.g., substantial 
amendment) prior to restarting treatment. Similarly, if an SAE occurs in the sentinel patients in a 
cohort, no additional patients will be dosed in that cohort until the safety data are reviewed. The 
Sponsor and/or contract research organization (CRO) will inform all sites in writing if 
enrollment and/or dosing is suspended. In addition, if enrollment is suspended, the interactive 
response technology (IRT) system will be adjusted such that no patients can be randomized to 
treatment until the safety review has been completed and a decision has been made to resume 
enrollment/dosing.  
4.4.5 
Considerations Due to COVID-19 Pandemic 
Due to the continuing COVID-19 pandemic, it is possible that modifications to the planned 
schedules of assessments may be necessary in response to local mandates, site closures, 
quarantines, travel limitations, etc. In light of the serious and progressive nature of HD and the 
lack of any alternative treatment options for patients, the Sponsor believes that patients may 
continue to participate in the study and receive investigational treatment provided that 
appropriate safety monitoring can be performed to ensure patient safety and protocol 
requirements can be met to ensure the overall scientific integrity of data collection. The 
following guidelines should be followed to ensure compliance in situations where trial conduct 
may need to be modified in response to the COVID-19 pandemic: 
Screening Activities: Screening activities may continue as long as local and institutional 
guidelines permit and if the protocol can be followed using the protocol-allowed visit windows. 
If this cannot be achieved, sites should temporarily halt screening new patients until local and 
institutional restrictions have been lifted.  
Informed Consent Forms: If the ICF cannot be signed in person due to COVID-19 restrictions, 
or in the case of re-consent due to study changes, the Investigator may review the ICF via video 
or phone call to the patient. A copy of the signed ICF should be provided in person at the next 
clinic visit or by a secure process in accordance with site practices and local regulations. Record 
of informed consent should be filed in the medical record. If a signed copy of the form cannot be 
obtained from the patient, the ICF should be reviewed in the presence of an impartial witness 
(who is with the patient), and a witness attestation should be filed in the medical record. In the 
event a photograph of the ICF is used, an attestation should be made in the medical record by the 
person entering the form as to how the photograph was obtained.  
Active Study Patients: Study dosing may continue as long as local and institutional guidelines 
permit, and safety monitoring is possible. If patients cannot be seen in clinic due to shelter-in 
place orders or institutional guidance, the Investigator should temporarily discontinue 


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administration of study drug and complete study visits that are amenable to remote or local 
assessments.  
For study visits with assessments that can be performed locally, the Investigator should make 
every attempt to have a local laboratory perform the tests, or assess whether a home health 
service is available to collect samples at a patient’s home by a trained nurse/phlebotomist. 
If patients cannot attend their scheduled dosing visit, it is preferable to administer the missed 
dose if it can be safely administered at a subsequent time point.  
All missed visits or changes to the study visit schedule outside of required visit windows due to 
COVID-19 should be noted as such in the electronic case report form (eCRF; Section 15.2.1). In 
addition, any changes to planned assessments due to the patient not being able to visit the clinic 
should be recorded as protocol deviations and marked “Due to COVID-19” (Section 15.3.2). 
Vaccination: WVE-003 does not target the immune system, so immune response to COVID-19 
vaccination is unlikely to be affected. Similarly, COVID-19 vaccination would not be expected 
to impact safety or efficacy of WVE-003. Investigators should consider the timing of dosing in 
the study with regard to timing of vaccination, when possible, so as to minimize the potential to 
confound interpretation of adverse events. 
5 PATIENT SELECTION AND WITHDRAWAL CRITERIA 
Approximately 54 patients will be enrolled. Patients will be randomized to a treatment arm/dose 
group only if they qualify according to all of the following inclusion and exclusion criteria. 
Patients will be required to be prescreened to determine heterozygosity at SNP3 with the 
A variant only on the same allele as the CAG triplet expansion.   
During Screening, patients who do not meet all remaining inclusion/exclusion criteria will be 
considered screen failures. Patients who screen fail may be rescreened, as appropriate, in 
consultation with the Medical Monitor and when approved by the Sponsor. 
5.1 
Inclusion Criteria 
1. Documented ability to understand the written study ICF(s) and consent and has 
provided signed written informed consent prior to any study procedures 
2. Ambulatory male or female 
3. Age ≥25 to ≤60 years old 
4. Body mass index ≤32 kg/m2 
5. Documented CAG triplet repeats ≥36 in the HTT gene 
6. Documented heterozygosity at SNP3 


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7. Documented presence of the A variant of SNP3 on the same allele as the pathogenic 
CAG triplet expansion 
8. Clinical diagnostic motor features of HD, defined as UHDRS Diagnostic Confidence 
Score = 4  
9. UHDRS TFC scores ≥9 and ≤13 
10. In the opinion of the Investigator, the patient is able to tolerate all study procedures, 
and is willing to comply with all other protocol requirements. 
11. Willingness to practice highly effective contraception for the duration of the study 
and for 5 months (i.e., 5 elimination half-lives) after the last dose of study drug, if 
patients or their partners are of childbearing potential. Non-childbearing potential and 
highly effective methods of contraception are defined in (Section 5.2.1.1 and 
Section 5.2.1.2). In addition, willingness to forego sperm or ova (egg) donation for the 
duration of the study and 5 months after completion of the study. 
5.2 
Exclusion Criteria 
1. Malignancy or received treatment for malignancy, other than treated basal cell or 
squamous cell carcinoma of the skin, within the previous 5 years 
2. Positive for Hepatitis B virus (HBV) or Hepatitis C virus (HCV). 
3. Known to be positive for human immunodeficiency virus (HIV). 
4. 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 
5. Previously received tominersen  
6. Received prior treatment with viral or cellular-based gene therapy  
7. Received any other study drug, including an investigational oligonucleotide, within 
the past 1 year or 5 half-lives of the drug, whichever is longer, with the exception of the 
following:   
a. Received WVE-120101 within the last 3 months (i.e., 5 half-lives); or 
b. Received WVE-120102 within the last 3 months (i.e., 5 half-lives) 
8. Implantable CNS device that may interfere with ability to administer study drug via 
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9. History of substance abuse disorder (except nicotine) within 6 months prior to the 
Screening Visit 
10. Positive for opioids (unprescribed), cocaine, amphetamines, methadone, barbiturates, 
methamphetamine, or phencyclidine at the Screening Visit 
11. Started or changed dose for concomitant medication for the treatment of HD 
symptoms or psychiatric disorders within 30 days prior to the Screening Visit 
(concomitant medications that have been administered on a stable regimen for ≥30 days 
are permitted) 
12. 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 
13. Clinically significant laboratory abnormality at Screening 
14. Clinically significant abnormality at Screening ECG, including but not necessarily 
limited to a confirmed QT interval corrected for heart rate (QTc) ≥450 msec for males or 
≥470 msec for females 
15. 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. Mental status, psychiatric medical history, 
and eligibility for the study must be documented in the screening questionnaire. 
16. Bone, spine, bleeding, or other disorder that exposes the patient to risk of injury or 
unsuccessful lumbar puncture 
17. Inability to undergo brain MRI (with or without sedation)  
18. Deemed to be at significant risk for suicidal behavior based on any the following 
criteria: 
a. The opinion of the Investigator 
b. Answers “yes” to Actual Suicide Attempts or Suicidal Behaviors in the Suicidal 
Behaviors section of the C-SSRS with reference to a 2-year period prior to the 
Screening Visit 
c. Answers “yes” on any items in the Suicidal Ideation section of the C-SSRS with 
reference to a 6-month period prior to the Screening Visit 
d. Answers “yes” on any items in the Suicidal Ideation section of the C-SSRS at the 
Baseline Visit since the last visit (Screening Visit) 


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19. 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 
20. History of hypersensitivity to other antisense oligonucleotides and any other drug 
that, in the opinion of the Investigator, may preclude study participation. 
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, respectively.  
5.2.1.1 
Non-Childbearing Potential 
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 
• 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 patient 
• 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) 


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In addition, male participants must be required to use a condom, as contraception requirement, 
for the duration of the study and, at minimum, until 5 months (i.e., 5 elimination half-lives) after 
the last WVE-003 dose. 
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 treatment with study drug 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 study drug.  
5.3.1 
Withdrawal of Patients From the Study  
Patients must be withdrawn from the study for any of the following: 
• Patient’s withdrawal of consent 
• 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) 
In addition, the Sponsor may withdraw a patient from the study at their discretion and for any 
reason. 
Any patient for whom consent to participate in the study is withdrawn will be removed from 
further treatment and study observation immediately upon the date of request. It should be 
encouraged that these patients complete the early termination study procedures (Section 4.1.5) 
and observations at the time of withdrawal. All information, including the reason for withdrawal 
from the study, must be recorded in the eCRF and source documentation. 
5.3.2 
 Discontinuation of Study Drug 
A patient must permanently discontinue treatment with study drug for any of the following 
reasons: 
• The patient is withdrawn from the study (Section 5.3.1). 


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• The patient experiences a serious or intolerable AE (as defined in Section 9) 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 10)  
• Patients with renal, hepatic, platelets, clotting time, and inflammatory laboratory values 
that are severe (i.e., CTCAE Grade 3) or higher and/or considered clinically significant, in 
the opinion of the Investigator, will temporarily discontinue treatment and be retested every 
2 weeks until resolution of laboratory abnormalities. Patients with renal or hepatic laboratory 
values that are serious (i.e., CTCAE Grade 4) will be permanently discontinued from 
treatment and will be retested every 2 weeks until resolution. 
If a patient discontinues treatment, they will be encouraged to remain in the study to be 
monitored and to complete all study-related procedures, unless consent is withdrawn. Patients 
who discontinue treatment due to an AE (Section 9) or pregnancy (Section 10) may require 
longer follow-up. 
The reason for discontinuation of treatment with study drug 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 
Patients will be replaced in accordance with the requirements for dose escalation.   
6 INVESTIGATIONAL DRUG AND PLACEBO 
6.1 
Method of Assigning Patients to Investigational Drug or Placebo 
Patients who qualify according to all of the inclusion and exclusion criteria will be randomized 
into the study. Treatment will be assigned through randomization performed using a centralized, 
interactive voice/web response system. 


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6.2 
Dose and Investigational Drug/Placebo Administration 
6.2.1 
Identity of Investigational Drug 
6.2.1.1 
WVE-003 
WVE-003 will be provided as lyophilized powder for reconstitution and dilution for IT injection. 
WVE-003 for injection will be prepared by reconstituting and diluting the lyophilized powder 
with aCSF supplied by the Sponsor. Directions on reconstitution and dilution are provided in the 
Pharmacy Manual.  
Laboratory Code: WVE-003  
Chemistry: WVE-003 can be described chemically as the fully neutralized sodium salt of a 
3′→5′ linked mixed 2′-O-(2-methoxyethyl)-/2′-deoxy-/ 2′-O-methyl ribonucleic acid 
oligonucleotide 20 mer, containing a prescribed combination of stereodefined Sp and Rp 
phosphorothioate diester, stereodefined Rp N-(1,3-dimethylimidazolidin-2-ylidenyl) 
phosphoramidate diester, and phosphodiester internucleotide linkages. 
International Nonproprietary Name: Not yet assigned  
6.2.1.2 
Placebo 
Placebo will be aCSF provided by the Sponsor. It will be a sterile, preservative-free solution. 
Placebo will be visually identical in appearance to the WVE-003 injection solution and 
administered intrathecally in order to maintain the blind. Placebo will be administered in a 
volume of 20 mL. 
6.2.2 
Administration of Investigational Drug  
Study drug (WVE-003 or placebo) will be administered by IT injection by direct lumbar 
puncture using an atraumatic needle, and the total volume of the injection will be 20 mL. WVE-
003 will be diluted with aCSF provided by the Sponsor and administered in a volume of 20 mL, 
as described in the Pharmacy Manual. The lumbar puncture will be performed by a physician 
who is experienced in lumbar puncture procedure and drug administration and appropriately 
trained for the study. Within 1 week prior to the lumbar puncture, 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 8.2.8). Patients should not be sedated during administration of study 
drug. Imaging is allowed to guide lumbar puncture if needed. Detailed instructions on the 
procedure to be used for lumbar puncture are provided in the Study Operations Manual. 
Within approximately 15 minutes prior to administration of study drug, CSF samples will be 
collected for safety assessments (Section 8.2.8), concentration of WVE-003 (Section 8.3), and 
PD (Section 8.4), per the Schedule of Assessments. Additional CSF collected will be stored and 
used for research purposes. Approximately 20 mL of CSF total should be collected.  


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Immediately after each administration of study drug, all patients should be ambulatory and active 
for approximately 30 minutes postdose. The Investigator should note any weakness or fatigue 
during this period. In addition, formal physical examinations targeting the neurological system 
will be performed at the time points noted in the Schedule of Assessments. Any postdose SAEs 
will be monitored until resolution.  
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-003 will be supplied by the Sponsor as a lyophilized powder in clear glass vials. Artificial 
CSF (placebo and diluent for WVE-003) will be supplied in single-use vials provided by the 
Sponsor for investigational use only.  
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. Both the WVE-003 for injection and aCSF placebo contain no 
preservatives and should be administered without delay or within 4 hours of 
reconstitution/preparation.  
Partially used, unused, or damaged vials should be disposed according to Sponsor instructions. 
Details on reconstitution and administration are provided in the Pharmacy Manual.   
6.4.2 
Study 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 must also be recorded. Only trained 
site staff are permitted to treat study patients. A study monitor will review the accountability 
records.  


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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. 
7 BLINDING AND RANDOMIZATION  
7.1 
Blinding  
In order to maintain the blinding of the study drug (placebo or investigational product), all study 
personnel will be blinded to patient treatment assignment. Physicians, nurses, patients, and any 
study personnel performing patient assessments must NOT be informed of the patient’s treatment 
assignment except in the event of a medical emergency or as required by regulatory authorities 
(Section 7.2).  
The Sponsor and CRO staff directly responsible for the conduct of the study, the Investigator, 
and site staff will be blinded to treatment for the duration of the study until database lock. 
The pharmacy personnel will be unblinded to prepare doses of investigational product or placebo 
to ensure that the patient and the clinical site staff responsible for administering study drug and 
conducting assessments per the protocol remain blinded to study treatment. In addition, a clinical 
research associate will be unblinded to perform drug accountability. 
7.2 
Breaking the Blind 
7.2.1 
Unblinding for Medical Emergency 
A patient’s treatment assignment should remain blinded until the end of the study. However, in 
the event of a medical emergency when the medical treatment of the patient depends on knowing 
the study treatment the patient received, the treatment blind may be broken through the IRT 
system. The Investigator must document the reasons for unblinding in the patient’s source 
documents. The Investigator is strongly advised not to divulge the patient’s treatment assignment 
to any individual not directly involved in managing the medical emergency nor to personnel 
involved with the analysis and conduct of the study. 
7.2.2 
Recording the Unblinding 
If an unblinding occurs, the date on which the code was broken, together with the identity of the 
person responsible for breaking the blind, must be documented in the patient’s source 
documents. The unblinded treatment information will not be disclosed to the Sponsor. In 
consultation with the Medical Monitor and the Sponsor, the patient may be withdrawn from the 
study, if the blind is broken.  
The documentation should include, but is not limited to, the following information: 
• Patient information 


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• Reason for unblinding  
• Date and time of unblinding 
• Name of the person requesting/responsible for unblinding 
7.3 
Randomization 
Patients will be randomly allocated to either active or placebo treatment at their Baseline visit, in 
Period 1 if they enter in Period 1, or in Period 2 if they enter in Period 2. Patients who participate 
in both periods will receive the same treatment in Period 2 as they were randomized to receive in 
Period 1. 
8 METHODS OF ASSESSMENT AND ENDPOINTS 
8.1 Prescreening Assessments 
Blood samples will be taken at the prescreening visit to enable patient eligibility assessment 
using a 2-step assay.  
The assay will be validated and performed at Asuragen, Inc., Austin, Texas, or other subsidiary 
laboratories working under the Sponsor and Asuragen’s close supervision. In step 1 of the assay, 
HD patient blood samples would undergo 2 independent allele-specific long-range polymerase 
chain reaction (AS LR-PCR) reactions. Each reaction has primer pairs specific to the SNP3 
variant with nucleotides adenine (A) or guanine (G). Amplicons generated from each 
AS LR-PCR will proceed independently to step 2 of the assay. In step 2, CAG trinucleotide 
repeat length will be enumerated using Asuragen’s AmplideX® PCR/capillary electrophoresis 
(CE) HTT Kit, which is based on repeat primed polymerase chain reaction (RP-PCR) technology 
and tested on a genetic analyzer within the terms of its CE mark. The amplicons from each 
reaction resultant from step 1 will be used for enumerating CAG repeat lengths on wtHTT and 
mtHTT alleles (also referred to as “phasing”). 
Only samples from AS LR-PCR with primer pair capable to amplify nucleotide “A” at SNP3 
position and, when further analyzed in step 2, the amplicon is shown to be only mutant HTT 
allele with required CAG repeat length will be identified as phased eligible. 
Patients confirmed to carry the A isoform of SNP3 on the same allele as the pathogenic CAG 
expansion will be qualified to undergo further screening for confirmation of eligibility. 
Investigators and patients will be advised only as to whether the patient meets the prescreening 
criteria and will not be provided with specific genetic test results (e.g., number of CAG repeats). 
All blood samples will be sent to central laboratories for processing, analysis, and verification. 
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 on sample collection, storage, processing, and shipping will be provided in 
the Laboratory Manual.   


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8.2 
Safety Assessments 
The safety assessments will include the following: 
• Adverse events (Section 9) 
• Medical history and demographics 
• Prior and concomitant medications 
• Physical examination (including neurological and psychiatric) 
• Height and weight 
• Vital signs 
• 12-lead ECG 
• Clinical laboratory evaluations (including clinical chemistry, hematology, and urinalysis) 
• Cerebrospinal fluid safety laboratory evaluation 
• Suicidality assessment 
• Pregnancy testing (if applicable) 
• Drug screening 
Any abnormal laboratory test results (hematology, clinical chemistry, or urine) or other safety 
assessments (e.g., vital sign measurements) that are clinically significant in the medical and 
scientific judgment of the Investigator are to be recorded as AEs or SAEs. 
8.2.1 
Medical History and Demographics 
A general medical history will be obtained at the Screening Visit. Investigator assessment of past 
medical history at Screening will include information regarding any significant medical, surgical, 
psychiatric, and/or neurological conditions and treatments.  
Prior HD treatments received, and other details about this condition will be recorded. In addition, 
education level will be recorded in accordance with the International Standard Classification of 
Education (1997).  
Demographic data will be collected and summarized for each treatment group. 


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8.2.2 
Prior and Concomitant Medications 
Medications with a start date before the first dose of study drug will be classified as prior 
medications. Any medication that the patient began taking after the first dose of study drug will 
be classified as concomitant. Any medication that a patient started before the first dose of study 
drug and continued to take during the study will be classified as both prior and concomitant. Any 
medication that was stopped on the same day as the first dose of study drug will be considered a 
prior medication. If the stop date of a given medication is missing, then the medication will be 
classified as concomitant. 
The minimum requirement is that the drug name, dose, indication, and the dates of 
administration are to be recorded. This will include all prescription drugs, herbal products, 
vitamins, minerals, and over-the-counter medications. Any changes in concomitant medications 
will also be recorded in the 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 the medication are recorded in full in the eCRF. 
8.2.3 
Physical Examination 
A complete physical examination will be performed at the time points noted in the Schedule of 
Assessments. The physical examination will include (but is not limited to) an examination of the 
head, eyes, ears, nose, throat, respiratory, cardiovascular, gastrointestinal, musculoskeletal, 
psychiatric, and neurologic systems, and neurologic (including mental status, cranial nerves, 
motor system, reflexes, coordination and gait, and sensory system) systems.  
At the postdose time points noted in the Schedule of Assessments, 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, upper and lower extremity measures of 
strength, tone, reflexes, and ambulation.   
Physical findings will be recorded in the eCRF and source documents. 
8.2.4 
Height and Weight 
The patient’s height and weight will be measured at the time points described in the Schedule of 
Assessments and recorded in the eCRF and source documents. 
8.2.5 
Vital Signs (Blood Pressure, Heart Rate and Temperature) 
Vital sign 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. 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 and recorded in the eCRF and source documents. As feasible, the same 


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position (either sitting or lying) should be used for all subsequent blood pressure 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.  
8.2.6 
12-Lead ECG 
Computerized, good quality, 12-lead ECGs will be collected and recorded at the time points 
described in the Schedule of Assessments. Recordings will be obtained in the supine position 
after the patient has rested comfortably for ≥10 minutes.  
The ECG tracing will be submitted and read by a centralized reviewer (details will be provided 
in a study-specific 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 and note the abnormality. 
8.2.7 
Clinical Laboratory Evaluations 
Clinical laboratory safety testing will be collected at the time points described in the Schedule of 
Assessments and recorded in the eCRF and source documents. 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 6. The full panel should include all 
parameters listed. Specific time points, as specified in the Schedule of Assessments, only require 
complete blood count (CBC), C-reactive protein (CRP), , complement, and fibrinogen. 


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Table 6 
Clinical Laboratory Assessments  
Hematology 
Coagulation 
Clinical chemistry 
Urinalysis 
Complete blood count, including: 
• White blood cell count (with 
differential when values are 
abnormal) 
• 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  
• Fibrinogen 
Activated partial 
thromboplastin time  
Prothrombin time  
International 
normalized ratio 
Sodium 
Potassium  
Chloride 
Bicarbonate 
Blood urea nitrogen  
Creatinine 
Creatine 
phosphokinase 
Alanine 
aminotransferase 
(ALT) 
Aspartate 
aminotransferase 
(AST) 
Alkaline phosphatase 
Bilirubin 
Urinalysis  
 
8.2.8 
Cerebrospinal Fluid Safety Laboratory Evaluation 
A CSF safety laboratory sample obtained at the times noted on the Schedule of Assessments will 
be evaluated at a local laboratory. All CSF samples should be collected using an atraumatic 
needle. The following parameters will be assessed: total protein, glucose, and cell counts and 
differential per local laboratory specifications.  
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 10 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 on 
sample collection, storage, processing, and shipping will be provided in the Laboratory Manual. 
8.2.9 
Suicidality Assessment (Columbia-Suicide Severity Rating Scale) 
The C-SSRS is a measure of suicidal ideations and suicidal behaviors35. The C-SSRS, provided 
in the Study Manual, consists of 2 forms: a form measuring symptoms at Screening 
(baseline/screening version) that includes a lifetime history and a form measuring symptoms 
since the last study visit (“since last visit” version). The baseline/screening form will be 
performed at the Screening visit, and the “since last visit” form will be performed at all later time 


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points, as described in the Schedule of Assessments. 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. 
8.2.10 
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. The serum pregnancy test will be determined by 
a central laboratory; urine pregnancy tests will be performed locally.  
8.2.11 
Drug Screening 
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. Drug screen tests will be evaluated by a central laboratory. 
8.3 
Pharmacokinetic Assessments  
Cerebrospinal fluid as well as plasma and urine samples for analysis of exposure to WVE-003 
will be collected at the time points specified on Schedule of Assessments. Samples will be 
collected at the following time points: 
Period 1 Plasma PK: Samples will be collected at all clinic visits during the Period 1 treatment 
phase. On Week 0/Day 1, samples will be collected predose (within 4 hours prior to dosing), and 
postdose at 30 minutes (±5 minutes), 1 hour (±15 minutes), 2 hours (±15 minutes), 4 hours 
(±30 minutes), 6 hours (±30 minutes) and 24 hours (±2 hours) postdose. On all clinic visits 
(Week 2, Week 4, Week 8, and Week 12), samples will be collected. A sample will also be 
collected at the early termination (ET) visit, if the patient discontinues early. 
Period 1 Urine PK: Samples will be collected on Week 0/Day 1 from 0-4 hours, 4-8 hours, and 
8-24 hours postdose. 
Period 1 CSF PK: Samples will be collected predose on Week 0/Day 1, as well as Week 2, 
Week 4, Week 8, and Week 12. A sample will also be collected at the ET visit, if the patient 
discontinues early. 
Period 2 Plasma PK: At the first and last dosing visit, blood samples will be collected predose 
(within 4 hours prior to dosing), and postdose at 30 minutes (±5 minutes), 1 hour (±15 minutes), 
2 hours (±15 minutes), 4 hours (±30 minutes), and 6 hours (±30 minutes). New patients only will 
also have a sample collected on Day 1 at 24 hours (±2 hours) postdose. For any other dosing 
visit, blood samples will be collected at 2 hours (±1 hour) postdose. In addition, plasma PK 
samples will be collected once at all non-dosing clinic visits. A sample will also be collected at 
the ET visit, if the patient discontinues early. 


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Period 2 CSF PK: Samples will be collected at all clinic visits (Week 0/Day 1, Week 4, 
Week 8, Week 12, Week 16, Week 20, Week 24, and Week 28). The sample will be collected 
predose on dosing visits. A sample will also be collected at the ET visit, if the patient 
discontinues early. 
The date and time of the sample collection will be recorded.   
Samples will be analyzed by a central laboratory to determine concentrations of WVE-003 using 
validated methods (plasma and CSF) or qualified methods (urine).   
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 10 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 Laboratory Manual.   
8.4 
Pharmacodynamic Assessments 
A CSF sample will be collected at the time points noted in the Schedule of Assessments to 
determine the change from baseline in concentration of mHTT protein. All CSF samples should 
be collected using an atraumatic needle. A plasma 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 NfL. In addition, the change from baseline in other measures of PD activity in 
CSF, plasma, or PBMCs will be assessed (e.g., tHTT, wtHTT, and NfL). Additional exploratory 
biomarkers (e.g., total tau) may also be evaluated.   
The study may utilize the method described by Wild et al36 or an alternative method to determine 
levels of mHTT protein. 
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 10 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 on 
sample collection, storage, processing, and shipping will be provided in the Laboratory Manual.   
8.5 
Immunogenicity Assessments 
Serum samples will be collected at the times noted on the Schedule of Assessments and analyzed 
at a central laboratory for measurement of anti-drug antibodies to WVE-003. 
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 Laboratory Manual.   


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8.6 
Magnetic Resonance Imaging  
A 3-Tesla MRI of the whole brain (without contrast) will be performed at the time points noted 
on the Schedule of Assessments. Sedation is permitted during the MRI.   
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 
MRIs of the brain will be characterized in patients receiving WVE-003. 
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. 
8.7 
Clinical Effects 
8.7.1 
Unified Huntington’s Disease Rating Scale  
The UHDRS is a research tool developed by the Huntington Study Group to provide a uniform 
assessment of the clinical features and course of HD37. The scale consists of 6 subtests, including 
motor assessment, cognitive assessment, behavioral assessment, an independence scale, 
functional assessment, and TFC, and is provided in the Study Manual. All subtests of the 
UHDRS should be performed except the behavioral assessment, as the PBA-s (Section 8.7.2) 
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 010 (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 alone. 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 high 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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8.7.2 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)38.  
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. The PBA-s is provided in the Study Manual. 
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 
study partner may also be interviewed as part of the PBA-s for this study if they are present at 
the visit.  
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 drug 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 will be followed until ET or end of 
study (EOS), at a minimum, or until the Investigator and the Sponsor agree that further follow-up 
is not required. Requirements for SAE follow-up are detailed in Section 9.3.3. 
An AE is defined as any untoward medical occurrence in a patient enrolled into this study 
regardless of its causal relationship to study drug. Patients will be instructed to contact the 
Investigator at any time after randomization if any symptoms develop. 
A TEAE is defined as any event not present before exposure to study drug or any event already 
present that worsens in either intensity or frequency after exposure to study drug.  
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 drug, action taken with 
respect to study drug, seriousness, any required treatment or evaluations, and outcome. All AEs 
will be followed until the ET or EOS visit, at a minimum. The sites will be provided with 
completion guidelines for the eCRF, which will further guide them on how to record the data, 
including AEs. The MedDRA will be used to code all AEs.  


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Any medical condition that is present at the time that the patient signs informed consent but does 
not worsen should not be reported as an AE. However, if it worsens at any time during the study, 
it should 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 in Table 7. 
Table 7 
Definitions of AE Severity Criteria 
AE Severity 
Definition  
Mild 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated. 
Moderate 
Moderate; of sufficient severity to make the patient uncomfortable; minimal, local, 
or noninvasive intervention indicated. 
Severe 
Severe or medically significant, of sufficient severity to cause the patient severe 
discomfort; may cause cessation of treatment; treatment of event 
symptoms/intervention may be required. 
Abbreviation: 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 intensity.  
9.2.2 
Relationship to Study Drug and/or Study Procedure 
The Investigator’s assessment of an AE’s relationship to study drug is part of the documentation 
process. All AEs, regardless of relationship, will be recorded in the eCRF. In addition, SAEs will 
be reported to regulatory authorities as required by local regulation (Section 9.3.4). In addition, 
the Investigator’s assessment of an AE’s relationship to study procedure should also be recorded.  


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The relationship or association of the study drug and/or study procedure in causing or 
contributing to the AE will be characterized using the classification and criteria presented in 
Table 8.  
Table 8 
Guidelines for Determining the Relationship (if Any) Between 
Adverse Event and the Study Drug and/or Study Procedure 
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 drug 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 drug seems likely. The event disappears or 
decreases on cessation of study drug. 
Possible 
This relationship suggests that the study drug 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 drug, but could also have been 
produced by other factors. 
Unlikely Related  
This relationship suggests an improbable (but not impossible) association between the 
study drug and the reported event. 
Not Related 
This relationship suggests no association between the study drug 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. Important medical events that may 
not result in death, be life-threatening, or require hospitalization may be considered SAEs when, 
based on 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 up until resolution. Serious 
AEs that occur after the final follow-up visit need not be reported unless the Investigator 
considers them related to study drug.  


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The Sponsor will provide a Sponsor causality statement for all SAEs.  
9.3.2 
Suspected Unexpected Serious Adverse Reactions 
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 adverse events (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 reactions, but if it did occur, would not be considered 
“unexpected” for SUSAR reporting. As an example, a flare-up of symptoms consistent with the 
underlying disease under treatment that required hospitalization would constitute a serious 
adverse reaction; however, the event would not be considered unexpected. An exception would 
be if the reporter believed that study drug worsened the underlying 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 site personnel first learn about the event using the 
SAE Report Form provided for the study. Regardless of causality, all SAEs that occur during the 
study (from the time the patient signs the ICF to the ET/EOS visit) must be reported to the 
Sponsor and recorded on the AE page of the patient’s eCRF and in the patient’s source 
documentation/medical file. Related SAE(s) that commence after the ET/EOS visit should be 
recorded in the patient's medical file and reported to the Sponsor but will not be added to the 
eCRF. 
The initial report should include at least the following information: 
• Study number 
• Patient’s identification number 
• Description of the event 


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• Date and time of onset of the event 
• Seriousness criteria 
• Causality assessment to study drug 
If follow-up is obtained or requested by the Sponsor and/or designee, the additional information 
should be emailed on an SAE Report Form to the Sponsor in a timely manner according to the 
procedures and timelines outlined above. Copies of discharge summaries, consultant reports, 
autopsy reports, and any other relevant documents may also be requested. 
The Investigator will be responsible for reporting all SAEs to the 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. 
PPD Pharmacovigilance Department 
Email: rtpsafety@ppd.com 
North America 
SAE Hotline: 1-800-201-8725 
SAE Fax line: 1-888-488-9697 
EMEA/APAC 
SAE Hotline: +44 (0) 1223-374240 
SAE Fax line: +44 (0)1223-374102 
9.4 
Overdose 
The study drugs are planned to be administered by trained study staff. Administration will be 
performed in accordance with the IB and instructions in a study-specific manual. Any incidence 
of overdose should be recorded as an SAE.  
No clinical data are available regarding overdose with WVE-003. 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 drugs. 


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10 PREGNANCIES 
If a patient becomes pregnant during the course of the study, the pregnancy must be reported, 
and monitoring of the patient and child should be conducted until the pregnancy outcome.  
If a female patient becomes pregnant during the study, she must be discontinued from the 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. The 
patient should be followed until the outcome of the pregnancy is known. 
Pregnancy in and of itself is not an SAE. However, 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. 
11 STATISTICAL METHODS 
A separate statistical analysis will be performed for Period 1 (SAD) and Period 2 (MAD). 
Patients receiving placebo will be pooled to form a placebo control group for Period 1 and 
Period 2. 
11.1 Sample Size Determination 
The sample size was not calculated on the basis of statistical hypothesis testing; however, the 
number of patients is sufficient for a Phase 1b/2a assessment of safety, tolerability, PK, and early 
measures of PD and clinical effects.   
11.2 Disposition of Patients 
Screened patients are defined as any patient who signed informed consent. Randomized patients 
consist of all patients, with a signed informed consent, randomized via the IRT. 
11.2.1 
Analysis Populations 
The following study populations will be evaluated:  
• Safety population: randomized patients who receive at least 1 dose of study treatment. 
• Pharmacokinetic population: the subset of the safety population with at least 1 postdose 
PK measurement 
• Pharmacodynamic population: the subset of the safety population with at least 1 postdose 
PD measurement 


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• Clinical efficacy population: the subset of the safety population with at least 1 postdose 
measurement 
11.3 Statistical Methods 
Summary statistics (n, mean, standard deviation [SD], median, minimum and maximum values 
for continuous variables, and number [%] of patients in each category for categorical variables) 
will be provided by dose group and visit. Baseline for the Period 2 analysis of clinical effects and 
pharmacodynamic endpoints will be the measurement prior to the first dose of study drug in 
Period 2 for both new Period 2 patients and Period 1 rollover patients. Sensitivity analysis will 
include using the measurement prior to first dose in Period 1 for the Period 1 rollover patients.   
11.3.1 
Study Drug Exposure and Compliance 
The extent of study drug exposure and compliance will be summarized by dose group for the 
safety population.  
11.3.2 
Analysis of Clinical Effects Endpoints 
The change from baseline of the clinical effects endpoints will be analyzed using a mixed model 
for repeated measures (MMRM). The MMRM will include the relevant baseline measure and 
factor variables for time, dose group and time by dose group interaction. An unstructured 
variance-covariance matrix will be used to model the within-subject variability. If the MMRM 
with unstructured variance-covariance matrix does not converge, a compound symmetric 
structure will be used. Least square means of the time and dose group combinations and contrasts 
to placebo will be provided with 95% confidence intervals and p-values.  
11.3.3 
Analysis of Pharmacodynamic Endpoints 
Pharmacodynamic biomarkers include (but are not limited to) mHTT, wtHTT, and NfL in the 
CSF and/or plasma. The NfL measurements will be log-transformed, and analysis will be based 
on the transformed data.   
The MMRM described for the analysis of the clinical effects endpoints will be applied with the 
exception that the baseline measure will not be included. 
11.3.4 
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 baseline value is defined generally as the last available value before randomization. 
• Adverse event observation periods are defined as follows: 
o Pretreatment AEs are AEs that developed or worsened prior to the first dose of 
study drug. 


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o On-treatment adverse events are AEs that developed or worsened from the first 
dose of study drug to study completion/discontinuation. Summaries of TEAEs 
will include all 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 treatment group. 
11.3.4.1 
Adverse Events 
Treatment-emergent AEs, TEAEs assessed as related to study drug or to study procedures, 
treatment-emergent SAEs will be summarized for each dose group based on MedDRA coding of 
verbatim terms reported by investigators. 
Adverse event incidence tables will present, by SOC and PT, the number and percentage of 
patients experiencing an AE, the number and percentage of patients experiencing an AE by 
severity and by relationship to treatment. 
Listings of all AEs, SAEs, deaths, and AEs leading to study discontinuation will be provided.  
11.3.4.2 
Clinical Laboratory Evaluations 
Summary statistics of laboratory variables will be calculated for each visit or study assessment 
by dose group. Shift tables of change from baseline will be provided.  
11.3.4.3 
Other Safety Evaluations 
Summary statistics of vital signs, ECG, and height and weight variables will be calculated for 
each visit or study assessment by treatment group. The C-SSRS will be summarized by study 
visit by treatment group. 
Anti-drug antibody assay results to WVE-003 will be described categorically. Summary statistics 
for anti-drug antibody titer results will be provided.  
11.3.5 
Analysis of Pharmacokinetic Variables 
The plasma and CSF WVE-003 concentration, and potentially WVE-003-related metabolite data 
will be summarized for patients in the PK population. Excreted urine amount over each 
collection interval and the total amount over 24 hours will also be summarized. 
For each patient in the PK population, the plasma WVE-003 concentration data will be analyzed 
by noncompartmental PK analysis. The parameters listed in Table 9 will be determined. 
Additional PK parameters may be evaluated if deemed appropriate. Pharmacokinetic parameters 
for each dose group will be summarized for each WVE-003 dose level and each visit. 


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Table 9 
Plasma Pharmacokinetic Parameters of WVE-003  
Parameter 
Definition 
Cmax 
Maximum observed concentration 
tmax 
Time of occurrence of Cmax 
AUClast 
Area under the plasma concentration-time curve from time zero to the last quantifiable 
concentration 
11.3.6 
Interim Analyses 
An unblinded interim analysis may be performed and the results summarized by dose group. The 
SAP will be finalized prior to the interim analysis. 
An SMC (Section 14.1) will be assembled to review the safety, tolerability, PK, and PD activity. 
Unblinded statisticians or designees who will not be involved in the study conduct will generate 
and distribute the data to the SMC prior to each SMC meeting. Details on the safety assessments, 
frequency of review, meeting schedules, and controlled access to unblinded data are outlined in 
the SMC charter.  
12 REGULATORY, ETHICAL, AND LEGAL OBLIGATIONS 
12.1 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. 
12.2 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. 
12.3 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, ICF, 
and advertisements to be used for the recruitment of study patients and any other written 
information regarding this study to be provided to the patient must be approved by the IRB or 
EC. The 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 should identify the 
IRB/EC name and address, the clinical protocol by title or protocol number or both, and the date 
of approval or when the 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 1 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. 
12.4 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 
nonroutine procedure that involves risk to the patient.  
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 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. 
The Investigator will retain the signed original ICF(s) and give a copy of the signed original 
form(s) to the patient. 
12.5 Privacy 
The Sponsor and Investigator(s) will ensure that this study is conducted in accordance with the 
most recent version of the applicable privacy laws, including local privacy laws. Additional 
information on how the Sponsor handles privacy can be found at 
https://wavelifesciences.com/privacy/. 
13 INVESTIGATOR’S OBLIGATIONS 
The following administrative items are meant to guide the Investigator in the conduct of the 
study in accordance with GCP guidance. 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. 
13.1 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 


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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. 
13.2 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 CFR by providing the following essential documents, including but not limited to 
the following: 
• 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 
13.3 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 
on publicly available clinical study registers in accordance with all national, state, and local laws 
or regulations. 
13.4 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. 


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13.5 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. 
13.6 Investigator’s Final Report 
When applicable, the Investigator should inform the institution of study completion; the 
investigator/institution should provide the IRB/EC with a summary of the study outcome and the 
Sponsor and regulatory authority(ies) with any reports required. 
13.7 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. 
13.8 Publications 
All information regarding WVE-003 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-003 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/Clinical 
Advisory Committee will be formed (Section 14.4) to oversee any publication or presentation of 
the study results. Subsequently, individual Investigators may publish results from the study in 
compliance with their agreements with the Sponsor. A prepublication manuscript is to be 
provided to the Sponsor at least 45 days prior to the submission of the manuscript to a publisher. 
14 STUDY COMMITTEES 
14.1 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 unblinded, aggregate safety data 


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periodically. In addition, the SMC will review SAEs that occur in the sentinel patients and 
TEAEs that meet the stopping criteria. The SMC will also review dose recommendations from 
the DEC. Unblinded information will be reviewed in a closed session without the Sponsor 
present. Details on safety reviews are provided in Section 4.4.   
Further details regarding the SMC, including committee membership, will be provided in a SMC 
Charter.   
14.2 Dose Escalation Committee 
The DEC will be responsible for making decisions regarding dose escalation in Period 1, 
selection of the initial dose level in Period 2, and subsequent dose escalation in Period 2. The 
DEC will review blinded data. This committee will include, but is not limited to, a Sponsor 
representative, a Medical Monitor, and a member of the Clinical Advisory Committee or Study 
Investigator. Details on safety reviews are provided in Section 4.4. Further details regarding the 
DEC, including committee membership, will be provided in a DEC Charter.  
14.3 Clinical Advisory Committee 
A Clinical Advisory Committee, consisting of a Study Investigator and experts in HD, will be 
formed to provide advice regarding protocol and study conduct.  
14.4 Publications Committee 
A Publications Committee, consisting of Investigators participating in the study, at least 
1 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.   
15 STUDY MANAGEMENT 
15.1 Monitoring 
15.1.1 
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) or as appropriate per local regulations. 
• 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 the 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. 
15.2 Data Quality Assurance 
15.2.1 
Electronic Case Report Forms and Data Management 
Patient data will be captured in an electronic data capture system, Medidata RAVE®, provided by 
the Sponsor or designee. Data will be entered directly from the source documents to the eCRFs 
following the CRF Completion Guidelines. Source documents should be clear, complete, and 
accurate and should include all the details of study assessments performed per the protocol. The 
Investigator is responsible for ensuring that the data entered on the eCRFs are accurate and 
complete and all data are entered in a timely manner.  
Any missed visits, changes to study visit schedule, etc. due to COVID-19 considerations should 
be noted as such.  
The final eCRF data and audit trails will be archived in an electronic media and placed in the 
Investigator’s study file. 
15.2.2 
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 or as 
appropriate per local regulations. In the event of an audit, the Investigator agrees to allow the 
Sponsor, representatives of the Sponsor, or regulatory authorities access to all study records. 
The Investigator should notify the Sponsor promptly of any audits scheduled by any regulatory 
authorities and should promptly forward copies of any audit reports received to the Sponsor. 


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15.3 Management of Protocol Amendments and Deviations 
15.3.1 
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. 
15.3.2 
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 impact the completeness, accuracy, and/or reliability of the study data or that may 
significantly affect a patient'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. Any deviation from the 
study protocol that is due to COVID-19 considerations should be noted as such. 
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. 
15.4 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, which has given a positive 
assessment of the research. 
2. Severe noncompliance to this protocol as judged by the Investigator and/or the Sponsor 
3. Due to unforeseen circumstances that prevent continuation of the research (e.g., financial 
issue) 


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The end of the study is defined as the date on which the last patient completes the last visit 
(includes follow-up visit). 
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. 
15.5 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 in marketing applications meet the standards of the ICH 
Guideline E3: Structure and content of clinical study reports (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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