A Phase 2A, Randomized, Placebo-Controlled, Dose-Ranging Study to Evaluate the Safety and Efficacy of PTC518 in Subjects With Huntington's Disease
Phase: PHASE2
Conditions: Huntington Disease
Sponsor: PTC Therapeutics

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TITLE PAGE 
CLINICAL PROTOCOL 
A PHASE 2A, RANDOMIZED, PLACEBO-CONTROLLED, 
DOSE-RANGING STUDY TO EVALUATE THE SAFETY AND EFFICACY 
OF PTC518 IN SUBJECTS WITH HUNTINGTON'S DISEASE 
PTC518-CNS-002-HD 
05 OCTOBER 2023 
VERSION 6.0 
PTC THERAPEUTICS, INC. 
100 CORPORATE COURT 
SOUTH PLAINFIELD, NJ 07080 US 
Notice of Proprietary Information: This document contains confidential information owned by or in the 
possession/control of PTC Therapeutics, Inc. Except as may otherwise be permitted in writing, by accepting or 
reviewing these materials, you agree that this information should not be disclosed to others (except where required by 
applicable law) and should not be used for unauthorized purposes. In the event of an actual or suspected breach of this 
obligation, PTC Therapeutics, Inc. should be notified promptly.

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PROTOCOL IDENTIFIERS AND STUDY PERSONNEL 
PTC Therapeutics Substance Identifier 
PTC518 
EudraCT Number 
2021-003852-18 
Protocol Number 
PTC518-CNS-002-HD 
Protocol Version 
6.0 
Protocol Version Date 
05 October 2023 
Protocol Phase 
Phase 2a 
Protocol Title 
A Phase 2a, Randomized, Placebo-Controlled, 
Dose-Ranging Study to Evaluate the Safety and Efficacy 
of PTC518 in Subjects With Huntington’s Disease 
PTC Clinical Lead 
PTC Medical Monitor 
PTC Biostatistician 
PTC Study Manager 
 
 

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PTC THERAPEUTICS PROTOCOL APPROVAL SIGNATURES 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PTC Therapeutics, Inc. 
 
Date 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PTC Therapeutics, Inc. 
 
Date 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PTC Therapeutics, Inc. 
 
Date 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PTC Therapeutics, Inc. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
The eSignature page is located on the last page. 
 
Date 

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INVESTIGATOR’S AGREEMENT 
I have received and read the Investigator’s Brochure for PTC518. I have read the PTC518-CNS-
002-HD Protocol and agree to conduct the study as outlined. I agree to maintain the 
confidentiality of all information received or developed in connection with this protocol. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Printed Name of Investigator 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of Investigator 
 
 
 
 
 
 
 
 
 
 
Date 

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SYNOPSIS 
Name of Sponsor/Company: PTC Therapeutics, Inc. 
Name of Investigational Product: PTC518 
Name of Active Ingredient: PTC518 
Protocol Number: PTC518-CNS-002-HD  
Phase: 2a 
Country: Global 
Title of Study: 
A Phase 2a, Randomized, Placebo-Controlled, Dose-Ranging Study to Evaluate the Safety and 
Efficacy of PTC518 in Subjects With Huntington’s Disease 
Studied Period: 12 months of treatment and 6 months of follow-up 
Objectives: 
Primary Objectives: 
• Evaluate the safety of PTC518 compared with placebo in subjects with 
Huntington’s disease (HD) 
• Evaluate the pharmacodynamic (PD) effects of PTC518 through the reduction in 
blood total huntingtin (tHTT) protein levels 
Secondary Objectives: 
• Assess the effects of PTC518 on change in caudate volume via volumetric 
magnetic resonance imaging (vMRI) (key secondary) 
• Assess the effects of PTC518 on change in composite Unified Huntington’s 
Disease Rating Scale (cUHDRS) 
• Determine the effect of PTC518 on mutant huntingtin (mHTT) protein in 
cerebrospinal fluid (CSF) at Month 12 
• Determine the effect of PTC518 on blood mHTT levels at Month 12 
Exploratory Objectives: 
• Determine the effect of PTC518 on mHTT protein in CSF at Month 3 
• Determine the effect of PTC518 on blood mHTT levels at Month 3 
• Assess the effect of PTC518 on change in whole brain, and putamen volume via 
vMRI 
• Assess the effect of PTC518 on change in ventricular volume via vMRI 
• Assess change after 12 months of treatment in clinical scales 
• Determine the effect of PTC518 on huntingtin (HTT) mRNA in blood 
Pharmacokinetic Objective: 
• Evaluate the concentration of PTC518 in subjects with HD 
Endpoints: 
Safety Endpoints: 
• Safety profile as characterized by treatment-emergent adverse events (TEAEs), 
laboratory abnormalities, neurofilament light chain (NfL) levels in plasma and 
CSF, electrocardiogram (ECG), vital signs, 
 
, Columbia Suicide Severity Rating Scale 
(C-SSRS), and physical examination 
Primary Efficacy Endpoint: 
• Change from Baseline in blood tHTT protein at Month 3 

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Secondary Endpoints: 
• Change from Baseline in caudate volume as assessed via vMRI at Month 12 (key 
secondary) 
• Change from Baseline in cUHDRS scores at Month 12 
• Change from Baseline in blood tHTT protein at Month 12 
• Change from Baseline in CSF mHTT protein at Month 12 
• Change from Baseline in blood mHTT protein at Month 12 
Exploratory Endpoints: 
• Change from Baseline in CSF mHTT protein at Month 3 
• Change from Baseline in blood mHTT protein at Month 3 
• Change from Baseline in whole brain, putamen, and ventricular volume (as 
assessed by vMRI) at Month 12 
• Change from Baseline in Unified Huntington’s Disease Rating Scale (UHDRS) 
Total Functional Capacity (TFC) sub-score at Month 12 
• Change from Baseline in other UHDRS sub-scores including Total Motor Score 
(TMS), Symbol Digit Modalities Test (SDMT), and Independence Scale (IS) at 
Month 12 
• Change from Baseline in the short form of the Problem Behaviors Assessment 
(PBA-s) (substituting for the UHDRS Behavioral Examination) at Month 12 
• Change from Baseline in wearable accelerometer assessment Timed Up and Go 
(TUG), 2-minute walk distance, and postural sway at Month 12 
• Change from Baseline in the Functional Rating Scale (FuRST) 2.0 questionnaire at 
Month 12 
• Change over time in blood HTT mRNA 
• Change over time in plasma and CSF NfL 
Pharmacokinetic Endpoint 
• Plasma trough concentration (Ctrough) and accumulation ratio of PTC518 in plasma 
over time and accumulation ratio of PTC518 in CSF at Visits 5 through 8 
Study Design/Methodology: 
This is a Phase 2a randomized, placebo-controlled, dose-ranging study to evaluate the safety 
and efficacy of PTC518. The study will be composed of 2 groups (Stage 2 group and Mild 
Stage 3 group), further broken into 6 parts (Parts A, B, C, D, E, and F), each of which will 
consist of an active treatment arm and a placebo arm. The Stage 2 group will consist of Parts 
A, B, and C, and will include subjects who qualify as Stage 2 disease based on the 
Huntington’s disease Integrated Staging System (HD-ISS) criteria. The Mild Stage 3 group 
will consist of Parts D, E, and F, and will include subjects who qualify as Mild Stage 3 disease 
based on the HD-ISS criteria. 
Approximately 144 subjects who satisfy all enrollment criteria at Screening will undergo 
Baseline evaluations and be randomized to Parts A, B, D, or E (depending on their stage of 
disease, as described above), after which they will be randomized to treatment arms within 
Part A or D (5 mg or matching placebo) or Part B or E (10 mg or matching placebo) in a 2:1 
ratio (active treatment to matching placebo) for 12 months. A Data and Safety Monitoring 
Board (DSMB) will closely monitor the safety of subjects. As specified in the DSMB Charter, 
the DSMB will undertake an unblinded review of safety data from the 5 and 10 mg dosing 

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groups and provide a recommendation on when Parts C and F (20 mg or matching placebo) 
can be initiated. 
At that time, subjects will be randomized to any study Part that is currently open for 
enrollment (depending on their stage of disease) and then to either active treatment or placebo 
(in a 2:1 ratio) within that Part. 
Subjects will return to the clinic every month until Visit 5 (Month 3) and then quarterly until 
Visit 8 (Month 12). Upon completion of Visit 8 (Month 12), subjects will have the option to 
enroll in Study PTC518-CNS-004-HD, a Phase 2 long-term extension study, to receive 
PTC518.  
For subjects not enrolling in Study PTC518-CNS-004-HD, Visit 8 will be considered the End 
of Treatment visit, and there will be a Follow-Up Safety Visit (Month 13) via 
telephone/telehealth to collect adverse event data and an additional Follow-Up Safety Visit on 
Month 16 (ie, approximately 4 months after the last dose of study drug) to collect adverse 
events 
. A final Follow-Up Safety Visit will occur on 
Month 18 via telephone/telehealth to collect adverse event data. 
Sample Size Justification: 
The sample size calculation for each disease stage is based on mean change from Baseline in 
blood tHTT protein at Month 3 (primary endpoint) assuming PTC518 has the same effect on 
blood tHTT protein reduction. With an effect size of 0.85 (ie, the magnitude of treatment 
difference is 85% of one standard deviation), achievement of 85% power at 2-sided alpha level 
0.05 would require 24 subjects. Approximately 24 subjects will be randomized to each active 
treatment arm and approximately 36 additional subjects per disease stage will be randomized 
to placebo. An additional 18 subjects (per disease stage) may be randomized to the maximum 
tolerated dose.  
Number of Subjects (Planned): 
Up to 252 adult male and female subjects (126 per disease stage) will be enrolled. 
Diagnosis and Main Criteria for Inclusion: 
Individuals eligible to participate in this study include those who meet all of the following 
inclusion criteria: 
1. Ambulatory male or female patient aged 25 years and older, inclusive 
2. Subject is willing and able to provide informed consent and comply with all protocol 
requirements. 
3. Genetically confirmed HD diagnosis with a cytosine-adenine-guanine (CAG) repeat 
length from 40 to 50, inclusive. CAG repeat length may be determined analytically 
through amplification. 
Eligibility for HD-ISS Stage 2 Group 
(Parts A, B, and C) 
4. A UHDRS IS score of 100 
5. A UHDRS TFC score of 13 
6. A score between 0.18 and 4.93 
inclusive on the normed version of the 
HD prognostic index (PINHD) 
Eligibility for HD-ISS Mild Stage 3 Group 
(Parts D, E, and F) 
9. A UHDRS TFC score of 11 or 12, or a 
UHDRS TFC score of 13 with an 
UHDRS IS score of <100 
7. Women of childbearing potential (WOCBP) must agree to use highly effective 
methods of contraception during dosing and for 6 months after stopping the study 
medication. Women of childbearing potential are defined as women who are fertile, 

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following menarche and until becoming postmenopausal unless permanently sterile. 
Permanent sterilization methods include hysterectomy, bilateral salpingectomy, and 
bilateral oophorectomy. A postmenopausal state is defined as no menses for 12 months 
without an alternative medical cause. A high follicle stimulating hormone (FSH) level 
in the postmenopausal range may be used to confirm a postmenopausal state in women 
not using hormonal contraception or hormonal replacement therapy. However, in the 
absence of 12 months of amenorrhea, a single FSH measurement is insufficient. 
Female partners of enrolled males who are of childbearing potential should consider 
use of highly effective methods of contraception while the enrolled male is taking 
study drug and for 6 months after stopping study drug. 
Highly effective contraception methods are defined as those that can achieve a failure 
rate of less than 1% per year when used consistently and correctly and include the 
following: 
• Combined (estrogen- and progestogen-containing) hormonal contraception 
associated with inhibition of ovulation: 
− Oral 
− Intravaginal 
− Transdermal 
• Progestogen-only hormonal contraception associated with inhibition of ovulation: 
− Oral 
− Injectable 
− Implantable 
• Intrauterine device 
• Intrauterine hormone-releasing system 
• Bilateral tubal occlusion 
• Vasectomized partner 
• Sexual abstinence 
In case of use of oral contraception, WOCBP should have been stable on the same pill 
for a minimum of 3 months prior to Screening. 
Abstinence is acceptable only as true abstinence when this is in line with the preferred 
and usual lifestyle of the subject. Periodic abstinence (eg, calendar, ovulation, 
symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of 
contraception. 
8. Sexually active and fertile males must use a condom during intercourse while taking 
study drug and for 6 months after stopping study drug and should neither father a child 
nor donate sperm in this period. A condom is required to be used also by vasectomized 
men in order to prevent potential delivery of the drug via seminal fluid. 

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Main Criteria for Exclusion: 
Individuals are not eligible to participate in this study if they have met or meet any of the 
following exclusion criteria: 
1. Inability or unwillingness to swallow oral tablets 
2. Receipt of an experimental agent within 90 days or 5 half-lives prior to Screening or 
anytime over the duration of this study, including RNA- or DNA-targeted HD-specific 
investigational agents (such as antisense oligonucleotides), cell transplantation, or any 
other experimental brain surgery 
3. Any history of gene therapy exposure for the treatment of HD 
4. Participation in an investigational study or investigational paradigm (such as 
exercise/physical activity, cognitive therapy, brain stimulation, etc) within 90 days 
prior to Screening or anytime over the duration of this study. Observational studies 
(such as ENROLL-HD) are not exclusionary. 
5. Presence of an implanted deep brain stimulation device 
6. 
7. Brain and spinal pathology that may interfere with CSF homeostasis and circulation, 
increased intracranial pressure (including presence of a shunt for the drainage of CSF 
or an implanted central nervous system catheter), malformations, and/or tumors 
8. Hospitalization for any major medical or surgical procedure involving general 
anesthesia within 12 weeks of Screening or planned during the study 
9. At significant risk of suicide as measured by the C-SSRS Baseline version with a 
moderate risk rating or higher score 
10. Risk of a major depressive episode, psychosis, confusional state, or violent behavior as 
assessed by the investigator 
11. Any medical history of brain or spinal disease that would interfere with the lumbar 
puncture process or safety assessments 
12. History of malignancy of any organ system (other than localized basal cell carcinoma 
of the skin or in situ cervical cancer), treated or untreated, within the past 5 years, 
regardless of whether there is evidence of local recurrence or metastases 
13. Any medical history or condition that would interfere with the ability to complete the 
protocol-specified assessments (eg, implanted shunt, conditions precluding magnetic 
resonance imaging scans) 
14. Antidepressant, antipsychotic, or benzodiazepine use, unless receiving a stable dose for 
at least 6 weeks prior to Screening and with a dose regimen that is not anticipated to 
change during the study. Benzodiazepine use for sedation for study-related procedures 
during the course of the study is permitted. 
15. History of illicit/illegal drug use, or alcohol use in the high-risk category of risk 
drinking levels according to the World Health Organization for a duration of 1 month 
or longer that in the opinion of the investigator could compromise the interpretability 
of study results 
16. Clinically significant medical condition, which in the opinion of the investigator could 
adversely affect the safety of the subject or impair the assessment of study results 
(eg, inability to fast or any known hypersensitivity to PTC518 or its excipients) 

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17. Current significant renal impairment defined as estimated glomerular filtration rate 
<60 mL/min/1.73 m2 at Screening 
18. Current hepatic impairment resulting in elevated liver function test (aspartate 
transaminase, alanine transaminase, alanine phosphatase) at 3 times the upper limit of 
normal at Screening 
19. Pregnancy, planning on becoming pregnant during the course of the study or within 
6 months of end of treatment, or currently breastfeeding 
20. Use of medications that are moderate or strong inhibitors of cytochrome P450 (CYP) 
3A4 within 1 week of Screening or medications that are moderate or strong inducers of 
CYP3A4 within 2 weeks of Screening or planned use of moderate or strong CYP3A4 
inhibitor or inducer medications during the study period 
21. A diagnosis of Juvenile-Onset Huntington’s Disease 
Investigational Product, Dosage and Mode of Administration: 
PTC518 tablets will be administered orally QD. The PTC518 active dosing arms will be 5 mg 
and 10 mg until the DSMB recommends initiation of a 20 mg dose as specified in the DSMB 
Charter. 
Duration of Treatment: 12 months 
Reference Therapy, Dosage and Mode of Administration: 
Matching placebo tablets will be administered orally QD. 
Criteria for Evaluation: 
Safety: 
Safety assessments will include observed TEAEs, clinical laboratory tests (including 
assessment of plasma and CSF NfL), vital signs, ECG, C-SSRS, 
, 
, and physical examination 
Efficacy: 
Blood tHTT protein (primary), vMRI (caudate volume; key secondary), cUHDRS (secondary), 
CSF mHTT protein (secondary), blood mHTT protein (secondary) 
Exploratory: 
CSF mHTT protein, blood mHTT protein, vMRI (whole brain, putamen, and ventricular 
volume), UHDRS (except behavioral), PBA-s, Opal wearable device, FuRST 2.0, blood HTT 
mRNA, plasma and CSF NfL, 
 
Pharmacokinetics: 
Pharmacokinetic assessment will include plasma Ctrough (Visits 3 through 8). Accumulation 
ratio will be calculated and reported in plasma (Visits 3 through 8) and CSF 
(Visits 5 through 8).  
Statistical Methods: 
A repeated measure analysis model (repeat on visit) will be used to compare each dose with 
placebo for blood tHTT protein levels. The model will include treatment, visit, treatment 
by-visit interaction and baseline blood tHTT, CAG, age, and CAG by age interaction as 
covariates. Nominal p values and 95% confidence interval for each pairwise comparison at 
Month 3 (active versus placebo) will be provided. The model will include disease stage (by 
PINHD bin for Stage 2 only and by TFC score for Mild Stage 3 only) as a stratification factor. 
The key secondary endpoint (change from baseline in caudate volume at Month 12) will be 
analyzed by a mixed model repeated measures (MMRM) model, using all available vMRI data 
up to the Month 12 Visit. The model will include fixed effects for treatment, baseline vMRI, 
and disease stage (by PINHD bin for Stage 2 only and by TFC for Mild Stage 3 only). The 

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intercept and time of collection will be included as a random effect nested withing subjects. 
The unstructured covariance matrix will be used in the model. The rate of changes will be 
compared between treatments and the least squares (LS) mean differences at Month 12 will 
also be provided. A similar model will be used for whole brain, putamen, and ventricular 
volume. 
For change from baseline in cUHDRS, a MMRM analysis (repeat at visit) will be performed 
using all data collected up to 12 months. The model will use treatment group, visits 
(categorical), treatment by-visit interaction, disease stage as fixed factors, age, CAG, and age 
by CAG interaction as covariates. The LS mean estimates for the change from Month 12, the 
difference between pairwise comparison with placebo, confidence intervals, and 2-sided 
p values will be presented. A similar model will be used for UHDRS sub-scores and PBA-s. 
Rate of changes in these scores will also be explored. 
For by disease stage analyses, PINHD category (0.180 to 0.679, 0.680 to 1.520, or 1.521 to 
4.930) will be used as fixed factor for Stage 2 only, and TFC score (11, 12, or 13) will be used 
as fixed factors for Mild Stage 3 only. 
The same analysis used for blood tHTT protein will be used for blood and CSF mHTT protein. 
Dose-response relationships will be explored. 
Demographic and baseline characteristics, disposition, safety, and efficacy endpoints will be 
summarized descriptively by dose group. Statistical models will be applied to understand the 
relationship between UHDRS components to blood and CSF assessments. 
Endpoints will be evaluated primarily with both disease stages combined, and by each disease 
stage. 
PTC Therapeutics (PTC) plans to conduct an interim analysis to confirm the pharmacokinetic 
(PK) and PD expectations and to evaluate safety when approximately 36 subjects from the 
5 mg dosing group (Parts A and/or D), and 36 subjects from the 10 mg dosing group (Parts B 
and/or E), including placebo, have completed 12 weeks of treatment.  
 

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TABLE OF CONTENTS 
TITLE PAGE ...................................................................................................................................1 
PROTOCOL IDENTIFIERS AND STUDY PERSONNEL ...........................................................2 
PTC THERAPEUTICS PROTOCOL APPROVAL SIGNATURES..............................................3 
INVESTIGATOR’S AGREEMENT ...............................................................................................4 
SYNOPSIS ......................................................................................................................................5 
TABLE OF CONTENTS ...............................................................................................................12 
LIST OF TABLES .........................................................................................................................16 
LIST OF FIGURES .......................................................................................................................17 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ................................................18 
1. 
INTRODUCTION ......................................................................................................20 
1.1. 
Study Rationale ...........................................................................................................20 
1.2. 
Overall Study Design ..................................................................................................22 
1.3. 
Risk/Benefit Assessment ............................................................................................24 
1.3.1. 
Summary of Safety Risks ...........................................................................................24 
2. 
STUDY OBJECTIVES AND PURPOSE ..................................................................26 
2.1. 
Primary Objectives .....................................................................................................26 
2.2. 
Secondary Objectives .................................................................................................26 
2.3. 
Exploratory Objectives ...............................................................................................26 
2.4. 
Pharmacokinetic Objective .........................................................................................26 
2.5. 
Safety Endpoints .........................................................................................................26 
2.6. 
Primary Efficacy Endpoint .........................................................................................26 
2.7. 
Secondary Endpoints ..................................................................................................26 
2.8. 
Exploratory Endpoints ................................................................................................27 
2.9. 
Pharmacokinetic Endpoint ..........................................................................................27 
3. 
INVESTIGATIONAL PLAN .....................................................................................28 
3.1. 
Number of Subjects ....................................................................................................28 
3.2. 
Treatment Assignment ................................................................................................28 
3.3. 
Dose Justification ........................................................................................................28 
3.4. 
Criteria for Study Termination ...................................................................................29 
3.5. 
End of Study Definition ..............................................................................................29 
3.6. 
Home Care Services ...................................................................................................30 
3.7. 
Unscheduled Visits .....................................................................................................30 

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4. 
SELECTION AND WITHDRAWAL OF SUBJECTS ..............................................37 
4.1. 
Subject Inclusion Criteria ...........................................................................................37 
4.2. 
Subject Exclusion Criteria ..........................................................................................38 
4.3. 
Screen Failures ............................................................................................................40 
4.4. 
Subject Discontinuation or Withdrawal ......................................................................40 
4.5. 
Enrichment Criteria ....................................................................................................40 
4.6. 
Lost to Follow-Up.......................................................................................................41 
5. 
TREATMENT OF SUBJECTS ..................................................................................43 
5.1. 
Description of Study Drug ..........................................................................................43 
5.2. 
Concomitant Medications ...........................................................................................43 
5.3. 
Treatment Compliance ................................................................................................43 
5.4. 
Randomization and Blinding ......................................................................................44 
6. 
STUDY DRUG MATERIALS AND MANAGEMENT ...........................................45 
6.1. 
Study Drug ..................................................................................................................45 
6.2. 
Study Drug Packaging and Labeling ..........................................................................45 
6.3. 
Study Drug Storage .....................................................................................................45 
6.4. 
Administration ............................................................................................................45 
6.4.1. 
Missed Doses and Overdoses .....................................................................................45 
6.5. 
Study Drug Accountability .........................................................................................45 
7. 
ASSESSMENT OF EFFICACY ................................................................................47 
7.1. 
Pharmacodynamic and Pharmacokinetic Parameters .................................................47 
7.1.1. 
Pharmacodynamic Parameters ....................................................................................47 
7.1.2. 
Pharmacokinetic Parameters .......................................................................................47 
7.2. 
Other Efficacy Assessments .......................................................................................47 
7.2.1. 
Volumetric Magnetic Resonance Imaging .................................................................47 
7.2.2. 
Unified Huntington’s Disease Rating Scale ...............................................................48 
7.2.3. 
Problem Behavior Assessment (Short Form) .............................................................48 
7.2.4. 
Opal Wearable Device Assessments ..........................................................................48 
7.2.5. 
Functional Rating Scale ..............................................................................................49 
8. 
ASSESSMENT OF SAFETY .....................................................................................50 
8.1. 
Safety Parameters .......................................................................................................50 
8.1.1. 
Demographic/Medical History ...................................................................................50 
8.1.2. 
Vital Signs ..................................................................................................................50 

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8.1.3. 
Weight and Height ......................................................................................................50 
8.1.4. 
Physical Examination .................................................................................................50 
 
 
8.1.6. 
Electrocardiogram .......................................................................................................51 
 
 
8.1.8. 
Laboratory Assessments .............................................................................................51 
8.1.9. 
Neurofilament Light Chain Levels .............................................................................51 
8.1.10. 
Columbia Suicide Severity Rating Scale ....................................................................52 
8.1.10.1. 
Virus Serology ............................................................................................................53 
8.1.10.2. 
Pregnancy Screen ........................................................................................................53 
8.2. 
Adverse Events, Serious Adverse Events, and Other Safety Reporting .....................53 
8.2.1. 
Definition of Adverse Events .....................................................................................53 
8.2.2. 
Definition of Serious Adverse Events ........................................................................54 
8.2.3. 
Adverse Events Reporting ..........................................................................................55 
8.2.4. 
Time Period and Frequency for Collecting/Reporting Adverse Event 
Information .................................................................................................................56 
8.2.4.1. 
Serious Adverse Event Reporting ...............................................................................56 
8.2.5. 
Method of Detecting Adverse Events and Serious Adverse Events ...........................57 
8.2.5.1. 
Assessment of Severity of Adverse Events ................................................................57 
8.2.5.2. 
Describing Adverse Event Relationship to Study Intervention ..................................58 
8.2.6. 
Follow-Up of Adverse Events and Serious Adverse Events ......................................59 
8.2.7. 
Regulatory Reporting Requirements for Serious Adverse Events .............................59 
8.2.8. 
Exposure During Pregnancy or Breastfeeding ...........................................................60 
8.2.8.1. 
Exposure During Pregnancy .......................................................................................60 
8.2.8.2. 
Exposure During Breastfeeding ..................................................................................61 
8.2.9. 
Cardiovascular and Death Events ...............................................................................61 
8.2.10. 
Disease-Related Events and/or Disease-Related Outcomes Not Qualifying as 
Adverse Events or Serious Adverse Events ................................................................61 
8.2.10.1. 
Progression of Underlying Disease ............................................................................61 
8.2.10.2. 
Abnormal Findings Associated With the Disease Being Studied ..............................62 
8.2.11. 
Contraceptive Guidance ..............................................................................................62 
8.2.11.1. 
Male Subject Reproductive Inclusion Criteria ...........................................................62 
8.2.11.2. 
Female Subject Reproductive Inclusion Criteria ........................................................62 

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8.2.11.3. 
Women of Childbearing Potential ..............................................................................63 
8.2.11.4. 
Contraception Methods ...............................................................................................63 
8.2.12. 
Adverse Events of Special Interest .............................................................................64 
8.2.13. 
Medication Errors .......................................................................................................64 
9. 
STATISTICS ..............................................................................................................65 
9.1. 
Subject Populations for Analysis ................................................................................65 
9.2. 
Sample Size Determination ........................................................................................65 
9.3. 
Statistical Methods ......................................................................................................65 
9.3.1. 
General Approach .......................................................................................................65 
9.3.2. 
Safety Analyses ..........................................................................................................66 
9.3.2.1. 
Adverse Events ...........................................................................................................66 
9.3.2.2. 
Laboratory Abnormalities ...........................................................................................66 
9.3.2.3. 
Other Safety Assessments ...........................................................................................66 
9.3.3. 
Efficacy Analyses .......................................................................................................66 
9.3.3.1. 
Analysis of the Primary Efficacy Endpoint ................................................................66 
9.3.3.2. 
Analysis of Secondary Endpoints ...............................................................................67 
9.3.3.3. 
Analysis of Exploratory Endpoints .............................................................................67 
9.3.4. 
Analysis of Pharmacokinetic Endpoints .....................................................................68 
9.3.5. 
Baseline Descriptive Statistics ....................................................................................68 
9.3.5.1. 
Disposition ..................................................................................................................68 
9.3.5.2. 
Demographics and Baseline Characteristics ...............................................................68 
9.3.5.3. 
Medical History and Prior Medication .......................................................................68 
9.3.6. 
Extent of Exposure and Concomitant Medications ....................................................68 
9.4. 
Planned Interim Analyses ...........................................................................................68 
9.5. 
Statistical Significance ................................................................................................68 
9.6. 
Missing Data ...............................................................................................................69 
10. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS.........................................70 
10.1. 
Study Monitoring ........................................................................................................70 
10.2. 
Audits and Inspections ................................................................................................71 
10.3. 
Safety Oversight .........................................................................................................71 
11. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................72 
11.1. 
Protocol Deviations ....................................................................................................72 
12. 
ETHICS ......................................................................................................................73 

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12.1. 
Ethics Review .............................................................................................................73 
12.2. 
Ethical Conduct of the Study ......................................................................................73 
12.3. 
Written Informed Consent ..........................................................................................73 
13. 
DATA HANDLING AND RECORDKEEPING .......................................................75 
13.1. 
Inspection of Records .................................................................................................75 
13.2. 
Retention of Records ..................................................................................................75 
13.3. 
Future Use of Stored Specimens and Data .................................................................76 
13.4. 
Data Protection ...........................................................................................................77 
14. 
PUBLICATION POLICY ..........................................................................................78 
15. 
PROTOCOL AMENDMENT HISTORY ..................................................................79 
15.1. 
Version 6.0: 05 October 2023 .....................................................................................79 
15.2. 
Version 5.0: 15 December 2022 .................................................................................80 
15.3. 
Version 4.0: 03 June 2022 ..........................................................................................82 
15.4. 
Version 3.0: 03 February 2022 ...................................................................................84 
15.5. 
Version 2.0: 09 December 2021 .................................................................................85 
16. 
REFERENCES ...........................................................................................................86 
17. 
APPENDICES ............................................................................................................88 
APPENDIX 1. RESTRICTED AND PROHIBITED MEDICATIONS .....................................88 
APPENDIX 2. WORLD HEALTH ORGANIZATION RISK DRINKING LEVELS ..............89 
 
LIST OF TABLES 
Table 3: 
Home Care Services for Subjects Unable to Have On-Site Visits at Month 1 
and Month 2 (Contingent on Approval of Principal Investigator and Medical 
Monitor) ......................................................................................................................30 
Table 4: 
Study Design and Schedule of Assessments ..............................................................32 
Table 5: 
Summary of Clinical Laboratory Tests .......................................................................52 
Table 6: 
Investigator Site Requirements for Recording/Reporting Adverse Events ................56 
Table 7: 
Grading of Adverse Events .........................................................................................57 
Table 8: 
Relationship of Study Intervention to Adverse Event ................................................58 
Table 9: 
Investigator Site Requirements for Recording/Reporting Medication Errors ............64 
 

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LIST OF FIGURES 
Figure 1: 
Study Design ...............................................................................................................23 
Figure 2: 
Randomization Schema ..............................................................................................23 

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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation or 
Specialist Term 
Explanation 
ADL 
Activities of daily living 
AE 
Adverse event 
AESI 
Adverse event(s) of special interest 
ALP 
Alkaline phosphatase 
ALT 
Alanine transaminase 
aPTT 
Activated partial thromboplastin time 
AST 
Aspartate transaminase 
AUC0-24 
Area under the concentration-time curve from 0 to 24 hours 
BAC 
Bacterial artificial chromosome (transgenic mouse model of Huntington’s disease) 
BSI 
Boundary Shift Integral 
CAG 
Cytosine-adenine-guanine 
CAP 
Cytosine-adenine-guanine-Age Product 
CRO 
Contract Research Organization 
CSF 
Cerebrospinal fluid 
C-SSRS 
Columbia Suicide Severity Rating Scale 
CTCAE 
Common Terminology Criteria for Adverse Events 
Ctrough 
Plasma trough concentration 
cUHDRS 
Composite Unified Huntington’s Disease Rating Scale 
CYP 
Cytochrome P450 
DSMB 
Data and Safety Monitoring Board 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
EDC 
Electronic data capture system 
EOS 
End of study 
EOT 
End of treatment 
ET 
Early Termination 
FSH 
Follicle-stimulating hormone 
FuRST 
Functional Rating Scale  
GCP 
Good Clinical Practice 
GGT 
Gamma-glutamyltransferase 
HCG 
Human chorionic gonadotropin 
HD 
Huntington’s disease 
HD-ISS 
Huntington’s disease Integrated Staging System  
HDL 
High-density lipoprotein 
HTT 
Huntingtin (protein) 
HTT 
Huntingtin (gene) 
ICF 
Informed consent form 
IEC 
Independent Ethics Committee 
INR 
International normalized ratio 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 
IS 
Independence Scale 
ITT 
Intent-to-Treat 
LDH 
Lactate dehydrogenase 
LDL 
Low-density lipoprotein 
LS 
Least squares  
MAD 
Multiple ascending dose 
MedDRA 
Medical Dictionary for Regulatory Activities 
mHTT 
Mutant huntingtin 
MMRM 
Mixed model repeated measures 

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Abbreviation or 
Specialist Term 
Explanation 
MRI 
Magnetic resonance imaging 
NCI 
National Cancer Institute 
NfL 
Neurofilament light chain 
NHP 
Nonhuman primate 
PBA-s 
Problem Behaviors Assessment (short form) 
PD 
Pharmacodynamic 
PIHD 
Huntington’s disease prognostic index 
PINHD 
Normed version of the Huntington’s disease prognostic index 
PK 
Pharmacokinetic(s) 
PP 
Per Protocol 
PT 
Prothrombin time 
RBC 
Red blood cell 
SAD 
Single ascending dose 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SDMT 
Symbol Digit Modalities Test 
SOP 
Standard Operating Procedure 
SUSAR 
Suspected unexpected serious adverse reaction 
TEAE 
Treatment-emergent adverse event 
TFC 
Total Functional Capacity 
tHTT 
Total huntingtin 
TMS 
Total Motor Score 
 
 
TUG 
Timed Up and Go 
UHDRS 
Unified Huntington’s Disease Rating Scale 
US 
United States 
vMRI 
Volumetric magnetic resonance imaging 
WBC 
White blood cell 
WOCBP 
Women of childbearing potential 
 

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1. 
INTRODUCTION 
Huntington’s disease (HD) is a rare, autosomal dominant, progressive, neurodegenerative 
disorder characterized by motor, cognitive, and psychiatric symptoms. Late-stage disease is 
marked by severe inability to walk, speak, swallow, or care for oneself, culminating in the need 
for full-time care and ultimately death, typically 15 to 18 years after the onset of symptoms 
(Caron 2020a). 
Huntington’s disease is a polyglutamine or “polyQ” disease caused by an expansion of the 
cytosine-adenine-guanine (CAG) trinucleotide repeat near the N terminus of the huntingtin 
(HTT) gene. This expansion leads to production of mutant huntingtin (mHTT) protein containing 
a polymorphic polyglutamine tract. The primary mechanism of HD pathogenesis is believed to 
be a toxic gain-of-function of mHTT, which leads to progressive neurodegeneration (Li 2006, 
Caron 2020a). In several nonclinical models of HD, reduction of mHTT improves HD 
neuropathology (Yamamoto 2000, Wang 2014, Evers 2018, Miniarikova 2018, Caron 2020b), 
thus confirming the importance of mHTT lowering as a therapeutic target in HD. Decreases in 
mHTT of between 
 are targeted for optimal therapeutic benefit, though decreases 
of 
 have been associated with potential therapeutic benefit (Garriga-Canut 2012, 
Kordasiewicz 2012, Lu 2013, Stanek 2014, Tabrizi 2019). 
The Huntington’s disease Integrated Staging System (HD-ISS) has been developed to help define 
cases of HD and provide a 4-part staging system that encompasses the full progression of the 
disease (Tabrizi 2022). The criteria for staging within this paradigm are as follows: 
• Stage 0: ≥40 CAG repeats 
• Stage 1: Features of Stage 0 with biomarkers of pathogenesis 
• Stage 2: Features of Stage 1 with clinical signs or symptoms 
• Stage 3: Features of Stage 2 disease with functional change. Stage 3 is further broken 
down by Mild, Moderate, and Severe. 
− Mild: Individuals who do not require assistance with routine activities, though 
these activities might be difficult to perform or take a long time. 
− Moderate: Individuals who require assistance with some routine activities. 
− Severe: Individuals who cannot do any routine activities independently. 
This study intends to enroll subjects who qualify as either Stage 2 or Mild Stage 3 disease. 
PTC518 is an orally bioavailable, proprietary small molecule being developed by 
PTC Therapeutics (PTC) for the treatment of HD. PTC518 modulates splicing of the HTT 
pre-mRNA, resulting in the inclusion of a pseudo exon (from within an intron) with premature 
termination codon that leads to the degradation of HTT mRNA and subsequent reduction in HTT 
protein levels. 
PTC518 thus represents a promising therapeutic for the treatment of HD. 
1.1. 
Study Rationale 
Prior to the development of this Phase 2a study, PTC518 was extensively evaluated in in vivo 
and in vitro nonclinical pharmacology models, in a comprehensive toxicology program, and in 

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Study PTC518-CNS-001-HD (Study CNS-001), a Phase 1 study in healthy volunteers. Together, 
the resulting data validate that PTC518 treatment results in dose-dependent pre-mRNA splicing 
and reduced protein levels, and that PTC518 treatment is safe and well tolerated in the clinic at 
single doses as high as 
 mg and multiple doses as high as 
 mg for 21 days. 
The present 12-month double-blind study with a 6-month Safety Follow-Up will allow for the 
quantification of the effect of PTC518 on total huntingtin protein (tHTT) reduction in subjects 
with HD and evaluation of the safety of PTC518 over 12 months of treatment. To mitigate 
potential risks to subjects, Part C, which includes the 20 mg dose, will not be initiated without 
Data and Safety Monitoring Board (DSMB) recommendation. 
The time course in untreated patients for HTT protein, mRNA, and other indicators of drug 
response in the blood is not available. The use of a concurrent placebo control allows for a direct 
assessment comparison to determine the effect of active treatment. In a disease state that does not 
have an approved disease modifying treatment option, such as HD, the inclusion of a placebo 
arm does not pose any ethical concerns. 
The patient population for this study was selected to reduce variability in an otherwise 
heterogeneous disease population by identifying subjects with active disease who either have not 
yet experienced functional decline (Stage 2) or have very limited features of functional decline 
(Mild Stage 3). This patient population was also selected as the population of subjects most 
likely to benefit from stabilization of disease from treatment with PTC518, being those with only 
limited functional decline due to disease progression. 
In this study, at randomization, subjects will thus be enrolled in the study based upon CAG 
repeat length and Baseline measures of the Symbol Digit Modalities Test (SDMT), Total Motor 
Score (TMS), Independence Scale (IS), and Total Functional Capacity (TFC). These factors will 
be used to identify and enroll subjects with active disease who have not yet experienced 
functional decline (Stage 2) or who have only very limited features of functional decline (Mild 
Stage 3), which may indicate a disease progression amenable to intervention. 
The Huntington’s disease prognostic index (PIHD) or its normed version (PINHD) score can be 
used to predict likelihood of HD progression. The PINHD score will be calculated at Screening to 
identify subjects eligible for participation in the Stage 2 group in the study, as it predicts 
progression into Stage 3. The Unified Huntington’s Disease Rating Scale (UHDRS) TFC and IS 
scores will also be calculated at Screening to identify subjects eligible for participation in the 
Stage 2 or Mild Stage 3 group in the study. 
Based on the kinetics of PTC518-mediated HTT lowering in humans, it is expected that the 
maximal extent of tHTT protein lowering in blood from patients with HD could be achieved 
between 4 and 6 weeks. The 12-month dosing regimen can further demonstrate that a 
steady-state decrease in blood tHTT levels is maintained over time with continued PTC518 
treatment. 
In addition to the primary endpoints of tHTT protein change from Baseline and safety, the 
present study includes exploratory clinical outcome endpoints to assess the effect of PTC518 on 
subjects’ cognition and motor function as measured by the UHDRS. The UHDRS has been 
extensively studied and developed to assess disease progression in multiple domains. The short 
form of the Problem Behaviors Assessments (PBA-s) has been included for assessment of 
disease progression in the behavioral domain. Cognitive impairment, motor function loss, and 

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accelerated brain volume loss in the caudate and putamen are key features of this disorder and 
have a notable impact on quality of life. The assessment of more sensitive and early motor 
changes via Opal wearable devices will also be included in this study as an exploratory endpoint. 
Studying these endpoints over 12 months will provide insight into the rate of change in earlier 
stages of disease and identify key measurements that may be early indicators of HD progression. 
1.2. 
Overall Study Design 
This is a Phase 2a randomized, placebo-controlled, dose-ranging study to evaluate the safety and 
efficacy of PTC518 and to determine the HTT protein lowering effect of these doses after 
12 months of treatment in subjects with HD. The study will be composed of 2 groups (Stage 2 
group and Mild Stage 3 group), further broken into 6 parts (Parts A, B, C, D, E, and F) each of 
which will consist of an active treatment arm and a placebo arm. The Stage 2 group will consist 
of Parts A, B, and C and will include subjects who qualify as Stage 2 disease based on the 
HD-ISS criteria. The Mild Stage 3 group will consist of Parts D, E, and F and will include 
subjects who qualify as Mild Stage 3 disease based on the HD-ISS criteria. 
Individuals who sign an informed consent form (ICF) will enter Screening to determine 
eligibility for the study. At Screening, potential subjects will have their gene mutation status 
confirmed by the investigator (either via historical gene sequencing or through an in-study gene 
sequencing assessment) and undergo additional evaluation to confirm they meet the enrollment 
criteria. 
Subjects who satisfy all enrollment criteria at Screening will undergo baseline evaluations and 
first be randomized to Part A, B, D, or E (depending on their stage of disease, as described 
above), after which they will be randomized to treatment arms within Part A or D (5 mg or 
matching placebo) or Part B or E (10 mg or matching placebo) in a 2:1 ratio of active treatment 
to matching placebo for 12 months. As specified in the DSMB Charter, the DSMB will 
undertake an unblinded review of safety data from the 5 and 10 mg dosing groups and provide 
recommendation on when Parts C and F (20 mg or matching placebo) can be initiated. 
At that time, subjects will be randomized to any study Part that is currently open for enrollment 
(depending on their stage of disease) and then to either active treatment or placebo (in a 2:1 
ratio) within that Part.  
Randomization will be stratified based on PINHD score for the Stage 2 group and by TFC score 
for the Mild Stage 3 group (Section 5.4). 
Once assigned treatment, subjects will take their assigned dose of study medication once a day. 
Subjects will be asked to return to the clinic every month after randomization until Visit 5 
(Month 3) and then quarterly until Visit 8 (Month 12) or receive home care services in lieu of 
in-person visits (Section 3.6) to undergo study assessments. On Month 12, subjects will take 
their final dose of study medication and complete the end of study (EOS) assessments. Upon 
completion of Visit 8 (Month 12), subjects will have the option to enroll in Study PTC518-CNS-
004-HD, a Phase 2 long-term extension study, to receive PTC518. 
For subjects not enrolling in Study PTC518-CNS-004-HD, Visit 8 will be considered the End of 
Treatment visit, and there will be a Follow-Up Safety Visit on Month 13 via telephone/telehealth 
to collect adverse events (AEs) and an additional Follow-Up Safety Visit on Month 16 
(ie, approximately 4 months after the last dose of study drug) to collect AEs 
 

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. A final Follow-Up Safety Visit will occur on Month 18 via 
telephone/telehealth to collect adverse event data. 
The safety profile will be characterized via the assessment of treatment-emergent adverse events 
(TEAEs) and serious TEAEs, laboratory abnormalities, neurofilament light chain (NfL) levels in 
in plasma and cerebrospinal fluid (CSF), and vital signs, the Columbia Suicide Severity Rating 
Scale (C-SSRS), electrocardiogram (ECG), 
 
, and physical examination. 
The primary efficacy assessment includes blood collection for tHTT protein at Month 3. 
Secondary efficacy assessments include volumetric magnetic resonance imaging (vMRI) for 
change in caudate volume (key secondary); other secondary efficacy assessments include blood 
and CSF collection for mHTT protein at Month 12, and cUHDRS scores. Exploratory 
assessments will include blood and CSF collection for mHTT protein at Month 3, clinical scales 
(UHDRS sub-scores [with the exception of the behavioral examination], PBA-s [substituting for 
the behavioral examination], and Functional Rating Scale [FuRST] 2.0); assessment of gait, 
balance, and postural sway via Opal wearable devices; plasma and CSF NfL; 
; and 
blood HTT mRNA. A complete Schedule of Assessments can be found in Table 4 and the study 
design is pictured in Figure 1. 
Figure 1: 
Study Design 
 
Abbreviations: ET, Early Termination 
Figure 2: 
Randomization Schema 
 
Note: *Enrollment for Parts C and F will only be initiated by recommendation of the DSMB following an unblinded 
review of safety data from the 5 and 10 mg dosing groups. 

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1.3. 
Risk/Benefit Assessment 
As described in previous sections, HD is a relentlessly progressive, neurodegenerative disorder. 
Early in the course of the disease, patients exhibit subtle symptoms; as the disease progresses, 
involuntary writhing movements become more pronounced, voluntary motor capabilities decline, 
and speech and swallowing are increasingly impaired, while aggressive and disinhibited behavior 
become more frequent. Late-stage disease is marked by severe inability to walk, speak, swallow, 
or care for oneself, culminating in the need for full-time care and ultimately death, 
typically 15 to 18 years after the onset of symptoms (Caron 2020a). 
There are currently no disease modifying interventions approved for use in HD; without 
intervention, the patient population to be included in this study will face continued progression, 
loss of function, and inevitably, death. The disease progression and mortality of the disease 
indicate that HD represents a high unmet medical need. Reduction of mHTT has been confirmed 
as an important therapeutic target. 
As described above, in Study CNS-001, multiple doses of PTC518 were associated with marked 
reductions in full-length HTT mRNA and HTT protein levels. Pharmacokinetic-
pharmacodynamic (PD) modeling based on interim data from Study CNS-001 have predicted 
that the exposures at the 5-mg and 10-mg doses will be associated with reductions of 
 
 in full-length HTT mRNA levels. Decreases in mHTT of between 
 are 
targeted for optimal therapeutic benefit, though decreases of 
 have been associated with 
potential therapeutic benefit (Garriga-Canut 2012, Kordasiewicz 2012, Lu 2013, Stanek 2014, 
Tabrizi 2019). In order to more fully characterize the safety and PD of PTC518 over 12 months 
of treatment, these 5-mg and 10-mg doses have been selected for Parts A and D and Parts B and 
E, respectively. A DSMB will closely monitor the safety of subjects. As specified in the DSMB 
Charter, the DSMB may recommend initiation of Parts C and F, with a 20-mg QD dose, which is 
anticipated to result in decreases in full-length HTT mRNA levels of approximately 
. It is 
anticipated that the selected doses will be associated with potential therapeutic benefit and the 
slowing of disease progression in this Phase 2a study. 
Study CNS-001 also provides evidence of PTC518 safety and tolerability at single doses ranging 
from 
 and multiple doses of 
 for durations of up to 21 days. In this 
study, PTC518 was safe and generally well tolerated. In both the single ascending dose (SAD) 
and multiple ascending dose (MAD) portions of the study, the overall incidence of AEs was 
comparable between subjects who received placebo and those who received PTC518. There were 
no events considered to be dose-limiting toxicities, and all AEs were resolved at the time of the 
interim analysis cut-off date. There were also no clinically significant laboratory abnormalities or 
ECG findings at any dose in either portion of the study. 
Based on the nonclinical and clinical data to date, PTC518 has a favorable risk/benefit profile in 
subjects with HD. For a detailed list of potential risks associated with PTC518 treatment, see the 
current Investigator’s Brochure. 
1.3.1. 
Summary of Safety Risks 
There are no important identified or important potential risks for PTC518. 

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For further details on each risk, risk mitigation strategies as well as adverse drug reactions 
recognized to date, and other important safety topics for PTC518, see Section 6 of the 
Investigator’s Brochure (IB), Summary of Data and Guidance for the Investigator. 
 

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2. 
STUDY OBJECTIVES AND PURPOSE 
2.1. 
Primary Objectives 
• Evaluate the safety of PTC518 compared with placebo in subjects with HD 
• Evaluate the PD effects of PTC518 through the reduction in blood tHTT protein 
levels 
2.2. 
Secondary Objectives 
• Assess the effects of PTC518 on change in caudate volume via vMRI (key secondary) 
• Assess the effects of PTC518 on change in composite Unified Huntington’s Disease 
Rating Scale (cUHDRS) 
• Determine the effect of PTC518 on mHTT protein in CSF at Month 12 
• Determine the effect of PTC518 on blood mHTT levels at Month 12 
2.3. 
Exploratory Objectives 
• Determine the effect of PTC518 on mHTT protein in CSF at Month 3 
• Determine the effect of P TC518 on blood mHTT levels at Month 3 
• Assess the effect of PTC518 on change in whole brain, and putamen volume via 
vMRI 
• Assess the effect of PTC518 on change in ventricular volume via vMRI 
• Assess change after 12 months of treatment in clinical scales 
• Determine the effect of PTC518 on HTT mRNA in blood 
2.4. 
Pharmacokinetic Objective 
• Evaluate the concentration of PTC518 in subjects with HD 
2.5. 
Safety Endpoints 
• Safety profile as characterized by TEAEs, laboratory abnormalities, NfL levels in 
plasma and CSF, ECG, vital signs, C-SSRS, 
, and 
physical examination 
2.6. 
Primary Efficacy Endpoint 
• Change from Baseline in blood tHTT protein at Month 3 
2.7. 
Secondary Endpoints 
• Change from Baseline in caudate volume as assessed via vMRI at Month 12 (key 
secondary) 
• Change from Baseline in cUHDRS scores at Month 12 

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• Change from Baseline in blood tHTT protein at Month 12 
• Change from Baseline in CSF mHTT protein at Month 12 
• Change from Baseline in blood mHTT protein at Month 12 
2.8. 
Exploratory Endpoints 
• Change from Baseline in CSF mHTT protein at Month 3 
• Change from Baseline in blood mHTT protein at Month 3 
• Change from Baseline in whole brain, putamen, and ventricular volume (as assessed 
by vMRI) at Month 12 
• Change from Baseline in UHDRS TFC sub-score at Month 12 
• Change from Baseline in other UHDRS sub-scores including TMS, SDMT, and IS at 
Month 12 
• Change from Baseline in the short form of the PBA-s (substituting for the UHDRS 
Behavioral Examination) at Month 12 
• Change from Baseline in wearable accelerometer assessment Timed Up and 
Go (TUG), 2-minute walk distance, and postural sway at Month 12 
• Change from Baseline in the FuRST 2.0 questionnaire at Month 12 
• Change over time in blood HTT mRNA 
• Change over time in plasma and CSF NfL 
2.9. 
Pharmacokinetic Endpoint 
• Plasma trough concentration (Ctrough) and accumulation ratio of PTC518 in plasma 
over time and accumulation ratio of PTC518 in CSF at Visits 5 through 8 

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3. 
INVESTIGATIONAL PLAN 
3.1. 
Number of Subjects 
Up to 252 adult male and female subjects will be enrolled (126 per disease stage). 
3.2. 
Treatment Assignment 
Treatment will be assigned via an Interactive Response Technology (IRT) after subject screening 
and eligibility is confirmed. Subjects will first be randomized to Part A or Part B or Parts D or E 
in a 1:1 randomization ratio, depending on their HD-ISS staging criteria (Section 4.1) and then to 
active treatment (5 mg in Parts A and D and 10 mg in Parts B and E) or matching placebo within 
each part in a 2:1 ratio of active treatment to placebo. As specified in the DSMB Charter, the 
DSMB will undertake an unblinded review of safety data from the 5 and 10 mg dosing groups 
and provide a recommendation on when Parts C and F (with a 20 mg active treatment arm) can 
be initiated. At that time, subjects will be randomized to any study Part that is currently open for 
enrollment, and then to either active treatment or matching placebo (in a 2:1 ratio) within that 
Part. An additional 18 subjects (per disease stage) may be randomized to the maximum tolerated 
dose. 
3.3. 
Dose Justification 
As described in Section 1, a 
 decrease in mHTT is the target as the range optimally 
associated with decreased pathology and anticipated therapeutic benefit in patients though it has 
been shown that reductions as low as 
 may be associated with potential therapeutic benefit 
(Garriga-Canut 2012, Kordasiewicz 2012, Lu 2013, Stanek 2014, Tabrizi 2019). 
In Study CNS-001, PTC518-mediated HTT pre-mRNA splicing was dose-dependent across all 
cohorts in both the SAD and MAD portions of the study. 
 
 
. On the basis of these clinical data, a pharmacokinetic (PK)-PD compartment 
model was used to simulate percentage of mRNA decreases (and thus the anticipated magnitude 
of HTT protein lowering) at additional potential clinical doses. 
 
 respectively, which are within 
the target range of reduction from baseline. Nonclinical data in a BAC (bacterial artificial 
chromosome) transgenic mouse model of HD showed a 
 
 
 
. 

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Evidence for the safety of the selected doses is provided by the Phase 1 trial, Study CNS-001, 
and the results of the comprehensive nonclinical toxicology program to date. In Study CNS-001, 
single doses ranging from 
 
 have been safe and generally well 
tolerated. In both SAD and MAD portions of the study, the overall incidence of AEs was 
comparable between subjects who received placebo and those who received PTC518. There were 
no events considered to be dose-limiting toxicities, and all AEs were resolved at the time of the 
interim analysis cut-off date. There were also no clinically significant laboratory abnormalities or 
ECG findings at any dose in either portion of the study. 
In the toxicology program conducted to date in rats and nonhuman primates (NHPs), a 
no-observed-adverse-effect level was identified in the 28-day rat and NHP studies, the 3-month 
rat and NHP studies, the 6-month rat study, and the 9-month NHP study (chronic studies). 
 
 
 
 
 
Thus, based upon the totality of the clinical and nonclinical safety data to date, and the 
anticipated reduction in HTT mRNA and HTT protein derived from clinical data and PK-PD 
modeling, the doses of 5, 10, and 20 mg are expected to be safe, well tolerated, and beneficial to 
subjects with HD. 
3.4. 
Criteria for Study Termination 
PTC reserves the right to discontinue the study prior to inclusion of the intended number of 
subjects. The investigator, after consultation with the medical monitor, reserves the right to 
discontinue the study at the investigator site for safety reasons at any time. 
Based on unblinded review of the safety data, the DSMB may recommend continuation of the 
study unchanged, study interruption, dose arm termination, study termination, modification of 
the study, or alteration in the DSMB monitoring plan. 
After a decision to terminate the study, investigators must contact all current study participants 
within a period set by PTC. As directed by PTC, all study materials must be collected, and all 
electronic data entry forms completed to the greatest extent possible. 
3.5. 
End of Study Definition 
The study will end when the last subject has completed the final assessment. 

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3.6. 
Home Care Services 
If for unforeseen reasons subjects are unable to have an on-site visit on Month 1 or 2, with 
approval from both the Principal Investigator and medical monitor, they may be offered an 
opportunity to have some study assessments performed in their home. In order to conduct the 
home visits, the subject must agree to utilize home care services. A licensed nurse will then 
contact the subject to schedule the visits. The home care nurse, the home care agency, and the 
home care services provider may have access to the subject’s personal data including their 
individually identifiable protected health information, such as the subject’s name, address, or 
phone number. This type of information will only be used as necessary to schedule and conduct 
the home visits and will not be provided to PTC. Table 3 outlines the assessments that may be 
done via home care services. 
Table 3: 
Home Care Services for Subjects Unable to Have On-Site Visits at Month 1 and 
Month 2 (Contingent on Approval of Principal Investigator and Medical Monitor) 
Month 1 and Month 2  
Home Health Visit 
Site Telephone/Telehealth Visit 
On-Site Visit 
Clinical laboratory assessments 
Blood HTT mRNA 
Blood HTT protein 
Plasma NfL 
PK 
Vital signs 
ECG 
Urine pregnancy test 
Concomitant Medications 
Adverse Events 
Drug accountability 
Dispense Study Drug (via local site 
procedures for shipment or 
couriered delivery) 
C-SSRS 
UHDRS 
Abbreviations: C-SSRS, Columbia Suicide Severity Rating Scale; ECG, electrocardiogram; HTT, huntingtin 
(protein): HTT, huntingtin (gene); NfL, neurofilament light chain; PK, pharmacokinetics; UHDRS, Unified 
Huntington’s Disease Rating Scale 
3.7. 
Unscheduled Visits 
Unscheduled visits are permitted at the investigator’s discretion. 
At minimum, adverse events and concomitant medications data must be collected at all 
unscheduled visits. Unscheduled visits may also include any of the following assessments, at the 
investigator’s discretion: 
• Physical examination 
• Body weight 
• Vital signs 
• Pregnancy test 
• Dispense study drug (if applicable) 
• Drug accountability 
• ECG 
• Blood HTT protein 
• Plasma NfL 

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• Clinical laboratory assessments 
• UHDRS Part II (SDMT only) 
• UHDRS Part V 
• UHDRS Part VI 
• C-SSRS 
In addition, if a subject is intended to enroll in the Phase 2 long-term extension study (Study 
PTC518-CNS-004-HD), but that study is not yet locally approved by regulatory and/or ethics 
authorities, the subject may continue within this study attending unscheduled visits 
approximately every 3 months prior to the end of study visit in order to ensure study treatment is 
not interrupted and to continue to assess safety parameters. Upon local approval of the Phase 2 
long-term extension study (PTC518-CNS-004-HD), the subject will return for the End of Study 
Visit and will transition into the long-term extension study. 

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Table 4: 
Study Design and Schedule of Assessments 
 
Screen 
ing 
Baseline 
Treatment Period 
Safety Follow-Up 
Notes 
 
Study Month 
Days -57 
to -8 
Days  
-22 to  
-1 
Day 
1 
Month 
1 
Month 
2 
Month 
3 
Month 
6 
Month 
9 
Month 
12 
/EOS/
EOT 
/ET 
Month 
13 
Month 
16 
Month 
18 
The Safety Follow-up 
visits must be 
performed for all 
subjects following 
either the EOT or ET 
visit. 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
 
Window (days) 
 
 
 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination 
X 
 
 
 
 
X 
X 
X 
X 
 
 
 
A complete physical 
exam will be performed at 
Visit 1 (Screening) and 
Visit 8/ET. A brief 
physical examination, 
including a neurological 
examination, will occur at 
all other timepoints.  
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant 
medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Body weight and 
height 
 
X 
 
X 
X 
X 
X 
X 
X 
 
 
 
Height will be collected at 
Baseline only. 
Vital signs 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Pregnancy test 
X 
X 
X 
 
(Monthly) 
For WOCBP, a serum 
HCG at Screening and 
Baseline. Urine HCG 
monthly from Day 1 
through the last Safety 
Follow-up Visit. For 
months where an on-site 
visit is not scheduled, 
subjects will complete a 
urine pregnancy test at 
home to be reported to 
the investigator and 
documented in the eCRF. 
Subjects will self-report 
all pregnancies through 
6 months after last dose 
of study drug. 
Randomization 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Dispense study drug 
 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
Drug accountability 
 
 
 
X 
X 
X 
X 
X 
X 
 
 
 
 

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Screen 
ing 
Baseline 
Treatment Period 
Safety Follow-Up 
Notes 
 
Study Month 
Days -57 
to -8 
Days  
-22 to  
-1 
Day 
1 
Month 
1 
Month 
2 
Month 
3 
Month 
6 
Month 
9 
Month 
12 
/EOS/
EOT 
/ET 
Month 
13 
Month 
16 
Month 
18 
The Safety Follow-up 
visits must be 
performed for all 
subjects following 
either the EOT or ET 
visit. 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
 
Window (days) 
 
 
 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
 
ECG 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Sample for genetic 
sequencing 
X 
 
 
 
 
 
 
 
 
 
 
 
Subjects with 
documentation of CAG 
repeat length are exempt 
from genetic sequencing 
requirements. CAG 
repeat length may be 
determined analytically 
through amplification. 
Plasma PK 
 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
Plasma samples will be 
taken predose and 4 (±2) 
hours postdose on Day 1 
(Visit 2) through Month 12 
(Visit 8). One additional 
plasma sample will be 
taken at Month 16 
(Visit 10).  
Blood HTT mRNA 
 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
On Day 1, only a predose 
sample is required. 
Subsequent samples 
should be collected at the 
same time as PK 
samples (ie, predose and 
4 [±2] hours postdose). 
An additional sample will 
be collected at Month 16 
(Visit 10). 

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Screen 
ing 
Baseline 
Treatment Period 
Safety Follow-Up 
Notes 
 
Study Month 
Days -57 
to -8 
Days  
-22 to  
-1 
Day 
1 
Month 
1 
Month 
2 
Month 
3 
Month 
6 
Month 
9 
Month 
12 
/EOS/
EOT 
/ET 
Month 
13 
Month 
16 
Month 
18 
The Safety Follow-up 
visits must be 
performed for all 
subjects following 
either the EOT or ET 
visit. 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
 
Window (days) 
 
 
 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
 
Blood HTT protein 
 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
On Day 1, only a predose 
sample is required. 
Subsequent samples 
should be collected at the 
same time as PK 
samples (ie, predose and 
4 [±2] hours postdose). 
An additional sample will 
be collected at Month 16 
(Visit 10).  
Plasma NfL 
 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
All samples to be drawn 
predose 
Clinical laboratory 
assessments 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
 
 
Safety laboratory 
assessments at Baseline 
should be performed 
fasted. All other safety 
laboratory assessments 
are not required to be 
performed fasted. 
Serology performed at 
Screening only. 
CSF collection  
 
X 
 
 
 
X 
X 
X 
X 
 
 
 
It is recommended that 
CSF collection be done at 
least 3 days prior to Day 
1. Sample collection may 
be done up to 8 days 
prior to Visits 5 through 8. 
CSF collection must be 
performed predose. 
UHDRS Part I (Motor 
Assessment) 
X 
 
X 
 
 
X 
X 
X 
X 
 
 
 
 
 
UHDRS Part II 
(Cognitive 
Assessment) 
X 
(SDMT 
only) 
 
X 
X 
(SDMT 
only) 
X 
(SDMT 
only) 
X 
(SDMT 
only) 
X 
(SDMT 
only) 
X 
(SDMT 
only) 
X 
 
 
 
At Screening, only SDMT 
is required to confirm 
eligibility. 
Only SDMT is done at 
Visits 3, 4, 5, 6, and 7. 
UHDRS Part IV 
(Functional 
Assessment) 
X 
 
X 
 
 
X 
X 
X 
X 
 
 
 
 

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Screen 
ing 
Baseline 
Treatment Period 
Safety Follow-Up 
Notes 
 
Study Month 
Days -57 
to -8 
Days  
-22 to  
-1 
Day 
1 
Month 
1 
Month 
2 
Month 
3 
Month 
6 
Month 
9 
Month 
12 
/EOS/
EOT 
/ET 
Month 
13 
Month 
16 
Month 
18 
The Safety Follow-up 
visits must be 
performed for all 
subjects following 
either the EOT or ET 
visit. 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
 
Window (days) 
 
 
 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
 
UHDRS Part V 
(Independence Scale) 
X 
 
X 
 
 
X 
X 
X 
X 
 
 
 
 
UHDRS Part VI 
(Functional Capacity) 
X 
 
X 
 
 
X 
X 
X 
X 
 
 
 
 
UHDRS Part VII 
(Clinical Summary) 
 
 
X 
 
 
X 
X 
X 
X 
 
 
 
 
UHDRS Part VIII 
(Clinical Disposition) 
 
 
X 
 
 
X 
X 
X 
X 
 
 
 
 
PINHD Calculation 
X 
 
 
 
 
 
 
 
 
 
 
 
TMS and SDMT will be 
performed at this visit to 
calculate PINHD. Only 
subjects who qualify for 
enrollment into the Stage 
2 group will have PINHD 
calculated. 
PBA-s 
 
 
X 
 
 
 
 
 
X 
 
 
 
The PBA-s will be used 
instead of Part III of the 
UHDRS. 
Timed Up and Go 
(TUG), 2-minute walk 
test, and postural 
sway test  
 
 
X 
 
 
X 
X 
X 
X 
 
 
 
The Opal wearable 
device will be worn during 
these assessments. Each 
test will be conducted 
twice: once with a 
concurrent cognitive 
interference task and 
once without. 
FuRST 2.0 
 
 
X 
 
 
X 
X 
X 
X 
 
 
 
 
vMRI 
 
X 
 
 
 
X 
 
 
X 
 
 
 
Imaging can be done up 
to 8 days prior to all vMRI 
visits after Screening. 

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Screen 
ing 
Baseline 
Treatment Period 
Safety Follow-Up 
Notes 
 
Study Month 
Days -57 
to -8 
Days  
-22 to  
-1 
Day 
1 
Month 
1 
Month 
2 
Month 
3 
Month 
6 
Month 
9 
Month 
12 
/EOS/
EOT 
/ET 
Month 
13 
Month 
16 
Month 
18 
The Safety Follow-up 
visits must be 
performed for all 
subjects following 
either the EOT or ET 
visit. 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
 
Window (days) 
 
 
 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Safety follow-up at Visit 9 
may be done by 
telephone/telehealth. 
Information about AEs 
will be collected from the 
signing of consent 
through 6 months after 
the last dose of study 
medication. 
C-SSRS 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
 
 
The “Baseline” version of 
the C-SSRS version will 
be used at Screening and 
Baseline. The “Since Last 
Visit” version of the 
C-SSRS will be used at 
all other timepoints. 
Abbreviations: AE, adverse event; CAG, cytosine-adenine-guanine; CSF, cerebrospinal fluid; C-SSRS, Columbia Suicide Severity Rating Scale; 
ECG, electrocardiogram; eCRF, electronic case report form; EOS, end of study; EOT, end of treatment; ET, Early Termination; FuRST 2.0, Functional Rating 
Scale; HCG, human chorionic gonadotropin; HTT, huntingtin (protein); HTT, huntingtin (gene); IS, Independence Scale; NfL, neurofilament light chain; PBA-s, 
short form of the Problem Behaviors Assessment; PINHD, normed version of the Huntington’s disease prognostic index; PK, pharmacokinetics; SDMT, Symbol 
Digit Modalities Test; TFC, Total Functional Capacity; TMS, Total Motor Scale; 
; TUG, Timed Up and Go; UHDRS, Unified 
Huntington’s Disease Rating Scale; vMRI, volumetric magnetic resonance imaging; WOCBP, women of childbearing potential 

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4. 
SELECTION AND WITHDRAWAL OF SUBJECTS 
The study will include approximately 24 subjects randomized to each active treatment arm, and 
up to 72 subjects randomized to placebo arm who satisfy all entry criteria. 
4.1. 
Subject Inclusion Criteria 
Individuals eligible to participate in this study include those who meet all of the following 
inclusion criteria: 
1. Ambulatory male or female patients aged 25 years and older, inclusive 
2. Subject is willing and able to provide informed consent and comply with all protocol 
requirements 
3. Genetically confirmed HD diagnosis with a CAG repeat length from 40 to 50, inclusive. 
CAG repeat length may be determined analytically through amplification. 
Eligibility for HD-ISS Stage 2 Group 
(Parts A, B, and C) 
4. A UHDRS IS score of 100 
5. A UHDRS TFC score of 13 
6. A score between 0.18 and 4.93 
inclusive on the normed version of 
the HD prognostic index (PINHD) 
Eligibility for HD-ISS Mild Stage 3 
Group (Parts D, E, and F) 
9. A UHDRS TFC score of 11 or 12, or 
a UHDRS TFC score of 13 with an 
UHDRS IS score of <100 
7. Women of childbearing potential (WOCBP) must agree to use highly effective methods 
of contraception during dosing and for 6 months after stopping the study medication. 
Women of childbearing potential are defined as women who are fertile, following 
menarche and until becoming postmenopausal unless permanently sterile. Permanent 
sterilization methods include hysterectomy, bilateral salpingectomy, and bilateral 
oophorectomy. A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause. A high follicle-stimulating hormone (FSH) level in the 
postmenopausal range may be used to confirm a postmenopausal state in women not 
using hormonal contraception or hormonal replacement therapy. However, in the absence 
of 12 months of amenorrhea, a single FSH measurement is insufficient. 
Female partners of enrolled males who are of childbearing potential should consider use 
of highly effective methods of contraception while the enrolled male is taking study drug 
and for 6 months after stopping study drug. 
Highly effective contraception methods are defined as those that can achieve a failure 
rate of less than 1% per year when used consistently and correctly and include the 
following: 
• Combined (estrogen and progestogen containing) hormonal contraception associated 
with inhibition of ovulation: 
− Oral 
− Intravaginal 

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−
Transdermal
•
Progestogen-only hormonal contraception associated with inhibition of ovulation:
−
Oral
−
Injectable
−
Implantable
•
Intrauterine device
•
Intrauterine hormone-releasing system
•
Bilateral tubal occlusion
•
Vasectomized partner
•
Sexual abstinence
In case of use of oral contraception, WOCBP should have been stable on the same pill for 
a minimum of 3 months prior to Screening. 
Abstinence is acceptable only as true abstinence when this is in line with the preferred 
and usual lifestyle of the subject. Periodic abstinence (eg, calendar, ovulation, 
symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of 
contraception. 
8. Sexually active and fertile males must agree to use a condom during intercourse while
taking study drug and for 6 months after stopping study drug and should neither father a
child nor donate sperm in this period. A condom is required to be used also by
vasectomized men in order to prevent potential delivery of the drug via seminal fluid.
4.2. 
Subject Exclusion Criteria 
Individuals are not eligible to participate in this study if they have met or meet any of the 
following exclusion criteria: 
1. Inability or unwillingness to swallow oral tablets
2. Receipt of an experimental agent within 90 days or 5 half-lives prior to Screening or
anytime over the duration of this study, including RNA- or DNA-targeted HD-specific
investigational agents (such as antisense oligonucleotides), cell transplantation, or any
other experimental brain surgery
3. Any history of gene therapy exposure for the treatment of HD
4. Participation in an investigational study or investigational paradigm (such as
exercise/physical activity, cognitive therapy, brain stimulation, etc) within 90 days prior
to Screening or anytime over the duration of this study. Observational studies (such as
ENROLL-HD) are not exclusionary.
5. Presence of an implanted deep brain stimulation device

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7. Brain and spinal pathology that may interfere with CSF homeostasis and circulation, 
increased intracranial pressure (including presence of a shunt for the drainage of CSF or 
an implanted central nervous system catheter catheter), malformations, and/or tumors 
8. Hospitalization for any major medical or surgical procedure involving general anesthesia 
within 12 weeks of Screening or planned during the study 
9. At significant risk of suicide as measured by the C-SSRS Baseline version with a 
moderate risk rating or higher score 
10. Risk of a major depressive episode, psychosis, confusional state, or violent behavior as 
assessed by the investigator 
11. Any medical history of brain or spinal disease that would interfere with the lumbar 
puncture processor safety assessments 
12. History of malignancy of any organ system (other than localized basal cell carcinoma of 
the skin or in situ cervical cancer), treated or untreated, within the past 5 years, regardless 
of whether there is evidence of local recurrence or metastases 
13. Any medical history or condition that would interfere with the ability to complete the 
protocol-specified assessments (eg, implanted shunt, conditions precluding MRI scans) 
14. Antidepressant, antipsychotic, or benzodiazepine use, unless receiving a stable dose for at 
least 6 weeks prior to Screening and with a dose regimen that is not anticipated to change 
during the study. Benzodiazepine use for sedation for study-related procedures during the 
course of the study is permitted. 
15. History of illicit/illegal drug use, or alcohol use in the high-risk category of risk drinking 
levels according to the World Health Organization for a duration of 1 month or longer 
that in the opinion of the investigator could compromise the interpretability of study 
results 
16. Clinically significant medical condition, which in the opinion of the investigator could 
adversely affect the safety of the subject or impair the assessment of study results 
(eg, inability to fast or any known hypersensitivity to PTC518 or its excipients) 
17. Current significant renal impairment defined as estimated glomerular filtration rate 
<60 mL/min/1.73 m2 at Screening 
18. Current hepatic impairment resulting in elevated liver function tests (aspartate 
transaminase [AST], alanine transaminase [ALT], alkaline phosphatase [ALP]) at 3 times 
the upper limit of normal at Screening 
19. Pregnancy, planning on becoming pregnant during the course of the study or within 6 
months of end of treatment, or currently breastfeeding 
20. Use of medications that are moderate or strong inhibitors of cytochrome P450 (CYP) 
3A4 within 1 week of Screening or medications that are moderate or strong inducers of 
CYP3A4 within 2 weeks of Screening or planned use of moderate or strong CYP3A4 
inhibitor or inducer medications during the study period (Appendix 1) 

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21. A diagnosis of Juvenile-Onset Huntington’s Disease 
4.3. 
Screen Failures 
Any subject who does not meet inclusion or exclusion criteria within the defined screening 
window prior to randomization will be considered a screen failure. Screen failures will be 
captured in the electronic data capture system (EDC). Screen failures may be rescreened after 
consultation with the medical monitor. 
4.4. 
Subject Discontinuation or Withdrawal 
Subjects will receive study treatment until protocol-specified study completion or treatment 
discontinuation for one of the reasons listed below. However, subjects may discontinue study 
treatment or withdraw their consent to participate in the study at any time without prejudice. In 
the event that a subject discontinues from the study prematurely, and unless consent is 
withdrawn, all efforts must be made to collect efficacy and safety data and to complete the Early 
Termination Visit (Visit 8). The following conditions require subject discontinuation from all 
study treatment: 
• At their own request 
• If a subject experiences an AE that is deemed related to treatment with PTC518 and 
in the investigator’s or PTC’s medical judgment continuation of treatment would be 
detrimental to the subject 
• At the specific request of a regulatory agency or DSMB for termination of treatment 
of an individual subject or all subjects under the protocol 
• Subject participation in another clinical study using an investigational agent or 
investigational medical device 
• Refusal of sexually active fertile subjects (excluding female subjects who have been 
sterilized) to use medically accepted methods of contraception 
• If a subject becomes pregnant 
• Significant noncompliance with the protocol in the opinion of the investigator or PTC 
• Any situation in which the investigator determines that the subject should not 
continue in the study 
The date PTC518 is discontinued and the reason for discontinuation will be recorded in the 
source documents and in the electronic case report form (eCRF). The medical monitor (and 
designee) must be informed via email when a subject discontinues study drug. 
When PTC518 is discontinued, the investigator is expected to perform all the evaluations 
according to the subject’s original schedule and as required at the Early Termination Visit and 
any additional evaluations that may be necessary to ensure that the subject is free of untoward 
effects. 
4.5. 
Enrichment Criteria 
Enrichment is defined as the prospective use of any patient characteristic to select a study 
population in which detection of a drug effect (if one is in fact present) is more likely than it 

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would be in an unselected population (FDA 2019). Due to the highly variable population of 
patients with HD, the enrichment strategy for this Phase 2a study is intended to select for 
subjects who have preserved capacity for activities of daily living, work, finances, and self-care, 
but have reduced performance on motor and cognitive tests and are predicted to experience 
functional impact on activities of daily living within 3 years. The TMS and SDMT from the 
UHDRS will be assessed at Screening (along with CAG repeat length and age) and used to 
identify this population via a validated HD prognostic index for pre-manifest patients with HD 
(Long 2017). 
The PIHD or its normed version (PINHD) can be used to predict likelihood of HD progression, 
with higher scores indicating greater risk of functional decline (Long 2017). Natural history 
survival curves generated using the PIHD show the disease trajectory in patients with a particular 
PIHD score. The PINHD score allows researchers to predict disease progression in a studied 
population with a high degree of certainty. 
Historically, disease progression was commonly indexed by the CAG-Age Product (CAP), 
which is a type of burden score of age and CAG expansion that has several variants. When CAP 
is supplemented with the TMS and SDMT from the UHDRS, predictive likelihood of HD 
progression increases. Using these enrichment criteria, a group of subjects with HD and no 
functional decline (measured via the TFC and IS) can be identified and changes in blood HTT 
levels after treatment can be measured. This group is likely to experience decline without 
HTT-lowering treatment as it has been found that earlier stages of HD are marked by increases in 
mHTT levels in CSF compared to controls (Ehrhardt 2021). 
At Screening, subjects’ cognitive and motor functions will be assessed by SDMT and TMS 
scores, respectively. Enrolled subjects who qualify for the Stage 2 group will present with no 
functional decline as assessed by the TFC and IS. Subjects in the Stage 2 group will be included 
in the study based on the calculation of PINHD scores as calculated by the IRT prior to 
randomization. Subjects with PINHD scores between 0.18 and 4.93 inclusive will be eligible for 
enrollment into the Stage 2 group in the study. The following formula will be utilized to 
calculate the PINHD score: 
PIHD=51(TMS)+(-34)SDMT+7 (age)(CAG-34). 
The PIHD score is converted to a normalized score using the following conversion: 
PINHD=(PIHD-883)/1044 
The Enroll-HD database (periodic data update 5) was utilized to identify the 0.18 to 4.93 range 
of PINHD scores for inclusion in the study. 
Subjects in the Mild Stage 3 group will qualify for enrollment if they present with a TFC score of 
11 or 12, or 13 with an IS score of <100. 
4.6. 
Lost to Follow-Up 
A subject is considered lost to follow-up if he or she does not complete the study and attempts to 
contact the subject are unsuccessful. Efforts must be made on the part of the site to avoid any 
subject being lost to follow-up during the study. Before any subject is considered lost to 
follow-up, a minimum of 2 documented telephone contact attempts and 1 certified letter within a 
week of the most recent planned study assessment must be sent in efforts to contact the subject. 

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After being considered lost to follow-up, a subject’s status may be changed if the subject makes 
contact at a later time provided the study is ongoing. 

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5. 
TREATMENT OF SUBJECTS 
5.1. 
Description of Study Drug 
PTC518 drug product is a solid dosage formulation for oral administration. See Section 6.1 for a 
full description of the study drug. 
5.2. 
Concomitant Medications 
Any treatments (including prescription and non-prescription drugs, health foods, herbal 
remedies, self-prescribed drugs, and street drugs) that are taken by a subject at Screening, during 
PTC518 administration, and for the remainder of the study are considered concomitant 
medications. Information regarding any concomitant medications will be collected and 
documented in the eCRF and in the source documents by the clinic staff. 
To the extent possible, administration of any prescription or over-the-counter drug products other 
than study medication should be minimized during the study period. Subjects should be 
discouraged from use of “health supplements” (eg, creatine, glutamine), herbal remedies, growth 
hormone, and self-prescribed drugs at any time during this clinical study of PTC518. If 
considered necessary for the subject’s well-being, drugs for concomitant medical conditions or 
for symptom management may be given at the discretion of the investigator. The decision to 
authorize the use of any other drug(s) should consider the subject’s safety, the medical need, the 
potential for drug interactions, the possibility for masking symptoms of a more relevant 
underlying event, and whether use of a concomitant medication will compromise the outcome or 
integrity of the study. 
Vaccination for the prevention of COVID-19 is permissible. The last dose of the vaccine must be 
received at least 2 weeks prior to visit assessments. 
Subjects and caregivers should be instructed about the importance of the need to inform the 
clinic staff of the use of any drugs or remedies (whether prescribed, over the-counter, or illicit) 
before and during the course of the study. The investigator is encouraged to consult the medical 
monitor or designee with questions relating to specific drugs and their potential for interactions 
with PTC518. 
5.3. 
Treatment Compliance 
Records of study drug used, dosages administered, and intervals between visits are kept during 
the study. Study drug accountability is performed on an ongoing basis by the study staff and 
checked by the monitor during site visits and at the completion of the study. 
Treatment compliance is defined as taking ≥80% of the medication over the course of the study. 
 

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5.4. 
Randomization and Blinding 
After subjects complete all baseline procedures on Day 1 and are eligible to be randomized, site 
staff will utilize an IRT system to assign study medication to each subject. Subjects will first be 
randomized to Parts A or B or Parts D or E in a 1:1 ratio, depending on their HD-ISS staging 
criteria (Section 4.1) after which they will be randomized to active treatment or placebo within 
each part in a 2:1 ratio of active to placebo. As specified in the DSMB Charter, a DSMB will 
undertake an unblinded review of safety data from the 5 and 10 mg dosing groups and provide 
recommendation on when Parts C and F, with a 20 mg active treatment arm, can be initiated at 
that time, subjects will be randomized to any study Part that is currently open for enrollment, and 
then to either active treatment or placebo (in a 2:1 ratio) within that Part. 
Enrollment for the Stage 2 group will be stratified by PINHD score, with the following 
stratification classes: 
• 0.180-0.679 
• 0.680-1.520 
• 1.521-4.930 
Enrollment for the Mild Stage 3 group will be stratified by TFC score, with the following 
stratification classes: 
• 11 
• 12 
• 13 
The randomization code will be kept strictly confidential and accessible only to the unblinded 
study statistician who is not directly involved in the conduct of the study. The study will be 
performed in a double-blind fashion. The investigator and study staff (including processing 
laboratory personnel), the subjects, and PTC’s staff will remain blinded to the treatment until 
after the database is locked. 
During the double-blind treatment period, the identity of the treatments will be concealed by the 
use of a placebo that is matched to the active drug in appearance, taste, odor, packaging, 
labeling, and schedule of administration. Unblinding will only occur in the case of subject 
emergencies before study completion and at the conclusion of the study. Except for emergency 
unblinding, individual subjects, parents/caregivers, and site personnel will not be informed of the 
randomized treatment assignments until the implications of revealing such data for the overall 
PTC518 clinical development program have been determined by PTC. 
Emergency unblinding should only occur after the investigator deems the subject’s emergency 
warrants the unblinding of the treatment. Unblinding of the treatment can only be performed by 
the investigator in the IRT system. Unblinding instructions are provided in the IRT system 
instruction manual. 

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6. 
STUDY DRUG MATERIALS AND MANAGEMENT 
6.1. 
Study Drug 
PTC518 drug product is a film-coated tablet dosage form for oral administration. PTC518 active 
and matching placebo tablets are white to off-white round coated tablets that will be provided in 
2 dosage strengths of 5- and 20-mg tablets. The placebo tablets contain the same compendial 
excipients and is manufactured in the same tablet sizes with the same appearance to match the 
respective 5-mg or 20-mg PTC518 tablets. 
6.2. 
Study Drug Packaging and Labeling 
The active and placebo tablets will be provided in cartons containing 5 blister cards. Each blister 
card will contain 21 tablets with a mix of PTC518 and/or matching placebo tablets. The labeling 
will comply with the applicable (local) laws and regulations. 
6.3. 
Study Drug Storage 
Study personnel must ensure that all study drug supplies are kept in a secure locked area with 
access limited to authorized personnel. Study drug must not be used outside the context of this 
protocol. Under no circumstances should the investigator or site personnel supply study drug to 
other investigators or clinics or allow study drug to be used other than as directed by this 
protocol. Only the trained study site personnel will handle the study drug dispensation and 
accountability. Refer to the pharmacy manual or clinical label for the storage conditions of the 
active and placebo. 
6.4. 
Administration 
Tablets of PTC518 or placebo will be administered orally, QD. The 4 dosing arms will include 
5 mg, 10 mg, 20 mg, or matching placebo for 12 months. 
Study drug will be taken by the subject orally, at home (except on days where the subject is 
instructed to take the dose in the clinic), in a single daily dose. Subject/caregiver must be 
instructed not to split the tablet(s) and subjects are instructed not to chew the study drug. All (3) 
tablets for the day should be taken either all at once (if tolerated) or one after another until all 
tablets are consumed. Tablets may be taken with or without food every day, at the same time 
each day. 
6.4.1. 
Missed Doses and Overdoses 
Study drug may be taken with or without food every day, at the same time each day starting at 
Visit 2 for the duration of the study. If a subject is late taking a dose of study drug, the dose 
should be taken as close to the usual time as possible in this case. PTC does not recommend 
specific treatment for an overdose of PTC518. The investigator will use clinical judgment to treat 
any overdose. Any overdose should be reported on the drug accountability log. 
6.5. 
Study Drug Accountability 
The investigator is responsible for keeping accurate records of the clinical supplies received from 
PTC or designee, the amount dispensed to and returned by the subjects, and the amount 
remaining at the conclusion of the study. 

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After confirmation by the study monitor, all unused investigational material (drugs and 
packaging) must be returned to PTC or its designee by the end of the study. If the Standard 
Operating Procedure (SOP) at any site states that the drug cannot be returned and must be 
disposed of on-site, PTC must review the SOP of that site prior to any final disposition done by 
site. Records documenting the date of study medication destruction or shipping, and amount 
destroyed or shipped should be kept. 
The Drug Accountability Records are considered as source data and will be archived at the site. 

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7. 
ASSESSMENT OF EFFICACY 
7.1. 
Pharmacodynamic and Pharmacokinetic Parameters 
Assessment of the PD and PK effect of PTC518 will be evaluated using the assessments outlined 
in the Schedule of Assessments (Table 4). Blood samples will be taken for PK, HTT mRNA, and 
HTT protein, which will be collected via vena puncture or via an intravenous catheter placed in a 
vein in the arm following the local standard procedures. Additionally, CSF samples will be 
collected by lumbar puncture, carried out by a qualified physician and in accordance with the 
local procedures. Information on equipment and further details on the sampling procedures, 
including volumes of blood and CSF to be collected, will be documented in a separate instruction 
laboratory manual. 
The total volumes of blood and CSF to be collected during the study are approximately 320 mL 
and up to 100 mL, respectively. 
7.1.1. 
Pharmacodynamic Parameters 
Pharmacodynamic parameters will include assessment of tHTT protein (in blood), HTT mRNA 
(in blood), mHTT protein (in CSF), and mHTT protein (in blood). 
7.1.2. 
Pharmacokinetic Parameters 
Sampling for PK analysis in plasma and CSF will be performed as described in Table 4.  
7.2. 
Other Efficacy Assessments 
7.2.1. 
Volumetric Magnetic Resonance Imaging 
The loss of brain tissue is a continuous variable of disease progression in HD. Volumetric 
magnetic resonance imaging will be used to effectively detect changes in brain volume during 
the study. 
Volumetric magnetic resonance imaging will be used to assess change over the treatment period 
using the Boundary Shift Integral (BSI). The BSI uses the shift in intensity differences on a pair 
of registered intensity-normalized images to quantify the difference between the 2 images. The 
BSI determines the total volume through which the boundaries of a given cerebral structure have 
moved and, hence, the volume change, directly from voxel intensities. This technique is 
considered the gold standard to measure global brain or regional atrophy (tissue loss). Using serial 
MRI scans, semi-automated region delineation with volume change is estimated using BSI, and 
will be used to validate vMRI changes (Prados 2015). The following brain areas will be assessed 
at Visit 2 (Baseline) and Visits 5 and 8: 
• Whole brain 
• Caudate 
• Putamen 
• Lateral ventricles 

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7.2.2. 
Unified Huntington’s Disease Rating Scale 
The UHDRS comprises 7 subscales with separate scoring for each part: 
• Part I is an assessment of motor function. Part I includes 31 items with a 5-point 
ordinal scale ranging from 0 to 4 with the highest score indicating inability to perform 
the motor task. The “Diagnosis Confidence Level” is also collected as a portion of the 
UHDRS Motor Assessment. 
• Part II is an assessment of cognitive function and includes 3 items with higher scores 
indicating better cognitive performance. The 3 items include a Verbal Fluency Test, 
SDMT, and Stroop Interference Test. In the Verbal Fluency Test, subjects are asked 
to enumerate either words beginning with a given letter within a limited amount of 
time (phonological fluency) or words within a given category, such as animals 
(semantic fluency). The SDMT is a symbol substitution neuropsychological test that 
examines a person’s attention and speed of processing. This test requires a person to 
substitute geometric symbols for numbers while scanning a response key. 
Oculomotor scanning, working memory, motor persistence, and visuomotor 
coordination are also required in order to score higher on the test. In order to prevent 
a learning effect from confounding the result of the SDMT, 3 different versions of the 
test will be administered at different timepoints for each subject. The Stroop 
Interference Test assesses the ability to selectively attenuate to specific items on the 
test, either word name or word color, when the 2 are interfering variables. 
• Part III is a behavioral assessment. The PBA-s will be substituted for this behavioral 
assessment in this study. 
• Part IV is a measure of functional capacity.  Huntington’s Disease Functional 
Capacity Scale is reported as the TFC, which has a total of 25 yes or no questions 
assessing the TFC of the individual. A score of 1 is given to all yes replies. 
• Part V is a measure of independence. The IS is measured on a scale from 10 to 100 
with higher scores indicating better functioning. 
• Part VI is a measure of functional capacity. Functional Capacity is measured using 5 
items with a 3- or 4-point ordinal scale ranging from 0 to 2 or 0 to 3 with the highest 
score indicating higher functional capacity. 
• Part VII is the clinical summary. An examination summary is performed by the 
examiner to take into account all aspects of the UHDRS. 
7.2.3. 
Problem Behavior Assessment (Short Form) 
The short form of the Problem Behavior Assessment is a semi-structured clinical interview that 
measures the occurrence and severity of 11 different behavioral symptoms in subjects with HD. 
7.2.4. 
Opal Wearable Device Assessments 
It has been noted in previous HD studies that bradykinesia, hypokinesia, gait speed, cadence, and 
increase in stride time are associated with HD decline. In order to assess changes in gait, balance, 
and postural sway, Opal wearable devices will be worn by the subject during 3, on-site 

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assessments: TUG in 3 m walkway, 2-minute walk distance, and a postural sway test. Each test 
will be conducted twice: once with a concurrent cognitive interference task and once without. 
7.2.5. 
Functional Rating Scale 
The FuRST 2.0 is a standardized HD-specific 24-item patient-reported outcome measure 
specifically designed to assess functional ability in pre-manifest and early-manifest HD. 

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8. 
ASSESSMENT OF SAFETY 
8.1. 
Safety Parameters 
The following have been defined as parameters regarding safety and tolerability: 
• Abnormalities in vital signs 
• Abnormalities in ECG parameters 
• Abnormalities in clinical laboratory tests 
• NfL levels in plasma and CSF 
• Changes in C-SSRS scores 
• TEAEs up to EOS 
• TEAEs leading to premature discontinuation of study drug 
• Treatment-emergent serious adverse events (SAEs) up to EOS 
• Abnormalities in physical examination 
8.1.1. 
Demographic/Medical History 
Demographic data and medical history will be collected at the times indicated in the Schedule of 
Assessments (Table 4). 
8.1.2. 
Vital Signs 
Supine blood pressure, supine pulse rate, respiration rate, body temperature, and oxygen 
saturation will be assessed at the timepoints indicated in the Schedule of Assessments (Table 4). 
Vital signs may also be performed at other times if judged to be clinically appropriate or if the 
ongoing review of the data suggests a more detailed assessment of vital signs is required. 
All measurements will be performed singly and repeated once if outside the relevant clinical 
reference range. Subjects must be supine for at least 5 minutes before blood pressure and pulse 
rate measurements. 
8.1.3. 
Weight and Height 
Body weight and height will be measured at the timepoints indicated in the Schedule of 
Assessments (Table 4). 
8.1.4. 
Physical Examination 
A complete physical examination will be performed at the timepoints specified in the Schedule 
of Assessments (Table 4). A complete physical examination includes general appearance, head, 
eyes, ears, nose, mouth, throat, thyroid, chest and lungs, abdomen, extremities, neuromuscular 
system, skin, and lymph nodes. 

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8.1.6. 
Electrocardiogram 
Subjects will be in a supine position for approximately 5 minutes prior to ECG measurements. 
Measurements will be taken at the times indicated in the Schedule of Assessments (Table 4) and 
will be classified as normal/abnormal. In case of a classification as “abnormal,” the abnormality 
will be described and its relevance in terms of clinical significance documented. The ECGs will 
be performed in triplicate. 
8.1.8. 
Laboratory Assessments 
A summary of clinical laboratory tests to be performed is presented in Table 5, with the timing of 
assessments as indicated in the Schedule of Assessments (Table 4). Clinically significant 
laboratory abnormalities which require clinical intervention or further investigation must be 
reported by the investigator as an AE or SAE as appropriate (Section 8.2.3). 
Safety blood samples will be taken under fasted conditions at Baseline. All other safety 
laboratory assessments are not required to be taken under fasted conditions. As a rule, the blood 
samples will be taken from the subject by puncture of a vein in the cubital or the antebrachial 
region. The samples will be sent to a central laboratory in accordance with specifications. 
8.1.9. 
Neurofilament Light Chain Levels 
The levels of NfL, a biomarker of neuronal injury, will be assessed in plasma and CSF as 
indicated in Table 4. 

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Table 5: 
Summary of Clinical Laboratory Tests 
Hematology 
Chemistry 
Urinalysisa 
Others 
CSF 
Hemoglobin 
Hematocrit 
RBC count 
Platelet count 
Mean corpuscular 
volume 
Mean corpuscular 
hemoglobin 
WBC count 
WBC differential 
Neutrophils 
Band neutrophils 
Eosinophils 
Monocytes 
Basophils 
Lymphocytes 
Urea 
Creatinine 
Glucose 
Sodium 
Potassium 
ALT 
AST 
GGT 
Bilirubin (total, direct 
and indirect) 
ALP 
Albumin 
Cholesterol (total) 
LDL 
HDL 
Triglycerides 
LDH 
Bicarbonate 
Calcium 
Chloride 
Total protein 
Uric acid 
Urobilinogen 
Nitrite 
pH 
Glucose 
Albumin 
Erythrocytes 
Leukocytes 
Ketones 
Microscopyb 
Specific gravity 
Bilirubin 
Pregnancy testc 
FSHd 
Serology (HIV, 
hepatitis B and 
hepatitis C)a 
Coagulation (PT [sec], 
PT [INR], aPTT) 
Urine drug screena 
Plasma NfL 
NfL 
WBCe 
RBCe 
Proteine 
Glucosee
Abbreviations: ALP, alkaline phosphatase; ALT, alkaline aminotransferase; aPTT, activated partial thromboplastin 
time; AST, aspartate aminotransferase; CSF, cerebrospinal fluid; FSH, follicle-stimulating hormone; GGT, 
gamma-glutamyltransferase; HDL, high-density lipoprotein; INR, international normalized ratio; LDH, lactate 
dehydrogenase; LDL, low-density lipoprotein; NfL, neurofilament light chain; PT, prothrombin time; RBC, red blood 
cell; WBC, white blood cell 
a Only during Screening. 
b Only if urine dipstick is positive and marked as at least ‘++’ for erythrocytes/leucocytes and albumin. 
c Serum pregnancy testing at Screening and Baseline; at other timepoints urine pregnancy testing is acceptable. For 
months when no in-person visit is scheduled, a home pregnancy test will be taken by the subject and reported to the 
investigator. 
d Required of postmenopausal females only during Screening. 
e Assessment of CSF WBC, RBC, protein, and glucose will be performed by local laboratories. 
8.1.10. 
Columbia Suicide Severity Rating Scale 
The C‐SSRS is a measure used to identify and assess individuals at risk for suicide. Questions 
are phrased for use in an interview format but can be completed as a self‐report measure if 
necessary. The C‐SSRS measures 4 constructs: suicidal ideation, the intensity of ideation, 
suicidal behavior, and lethality. It includes “stem questions,” which, if endorsed, prompt 
additional follow‐up questions to obtain more information. 
The C‐SSRS suicidal ideation construct comprises 5 categories, all of which maintain binary 
responses (yes/no) to indicate a presence or absence of ideation. The 5 categories included in the 
C‐SSRS ideation construct are as follows: 
Category 1 – Wish to be Dead; 
Category 2 – Non‐specific Active Suicidal Thoughts; 
Category 3 – Active Suicidal Ideation with Any Methods (Not Plan) without Intent to Act; 
Category 4 – Active Suicidal Ideation with Some Intent to Act, without Specific Plan; 

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Category 5 – Active Suicidal Ideation with Specific Plan and Intent 
The C-SSRS intensity of ideation construct is measured by evaluating on a 1 to 5 ordinal scale 
the following parameters: frequency, duration, controllability, deterrents, reason for and ideation. 
A yes/no binary response is also utilized in assessing suicidal behavior for the following 
categories: actual attempt, interrupted attempt, aborted attempt, preparatory acts or behavior, 
suicidal behavior, and suicide. Actual attempts are then scored based on their potential/actual 
lethality and/or medical damage. 
The outcome of the C‐SSRS is a numerical score obtained from the aforementioned categories.  
8.1.10.1. Virus Serology 
Virus serology (HIV, hepatitis B, and hepatitis C) will be assessed at the timepoints specified in 
the Schedule of Assessments (Table 4). 
8.1.10.2. Pregnancy Screen 
Pregnancy testing will be performed as indicated in Table 4. Subjects will complete a urine 
pregnancy test monthly from Day 1 through the last Safety Follow-Up either at the site or at 
home (for months where an on-site visit is not scheduled). All pregnancy tests will be 
documented in the source and eCRFs. 
Subjects will self-report all pregnancies through 6 months after last dose of study drug. 
8.2. 
Adverse Events, Serious Adverse Events, and Other Safety Reporting 
8.2.1. 
Definition of Adverse Events 
An AE is any untoward medical occurrence associated with the use of a study intervention in 
humans, whether or not it is considered related to the study intervention. An AE can therefore be 
any unfavorable and unintended sign (for example, an abnormal laboratory finding), symptom, 
or disease in a study subject who is administered with study intervention in this study. 
For this protocol, untoward medical occurrences that meet and do NOT meet the criteria of an 
AE include the following: 
Events Meeting the AE Definition 
• All AEs during the course of treatment with study intervention 
• All AEs resulting from medication misuse, abuse, withdrawal, or overdose of study 
drug 
• All AEs resulting from medication errors, such as dispensing or administration error 
outside of what is described in the protocol 
• Apparent unrelated illnesses, including worsening of a preexisting illness 
• Injury or accidents. Note that if a medical condition is known to have caused the 
injury or accident (a fall secondary to dizziness), the medical condition (dizziness) 
and the accident (fall) should be reported as 2 separate AEs. The outcome of the 
accident (hip fracture secondary to the fall) should be recorded in source documents. 

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• Abnormalities in physiological testing or physical examination findings that require 
clinical intervention or further investigation (beyond ordering a repeat [confirmatory] 
test) 
• Laboratory or ECG abnormalities that require clinical intervention or further 
investigation (beyond ordering a repeat [confirmatory] test) unless they are associated 
with an already reported clinical event 
Events NOT Meeting the AE Definition 
• Laboratory abnormalities associated with a clinical event should be captured in the 
source documents. Laboratory abnormalities not requiring clinical intervention or 
further investigation will be captured as part of overall laboratory monitoring and 
should not be reported as AEs. 
• The disease/disorder being studied or expected progression, signs, or symptoms of the 
disease/disorder being studied, unless more severe than expected for the subject’s 
condition (see Section 8.2.10). 
• Preexisting condition (eg, allergic rhinitis) must be noted on the appropriate eCRF for 
Screening but should not be reported as an AE unless the condition worsens, or the 
episodes increase in frequency during the AE reporting period. 
• Diagnostic and therapeutic noninvasive and invasive procedures, such as surgery, 
should not be reported as AEs, unless the medical condition for which the procedure 
was performed meets the definition of an AE. For example, an acute appendicitis that 
occurs during the treatment with study intervention should be reported as the AE, and 
the resulting appendectomy should be recorded in the source documents and eCRF. If 
a surgical procedure was planned prior to entry into the study, and the surgery is not 
performed because of a worsening of a baseline condition, this should not be reported 
as an AE. Note that, as described in Section 8.2.2, any hospitalization occurring as the 
consequence of an AE during the study period should be reported as an SAE. 
Each AE is to be classified as serious or nonserious by the investigator using medical and 
scientific judgment. 
Treatment of AEs will be symptom-based and at the discretion of the investigator. 
8.2.2. 
Definition of Serious Adverse Events 
An SAE is an untoward medical occurrence or effect at any dose, regardless of whether it is 
considered to be related to the study intervention, which results in one of the following: 
• Results in death. This includes all deaths on treatment or within 6 months after last 
study intervention administration, including deaths due to disease progression. Any 
death occurring later than 6 months following the last dose need not be reported as an 
SAE unless it is a result of an event that started within the period covered by the on-
study definition. The reported AE should be the event that caused the death. 
In addition, any AE resulting in death that occurs post the AE reporting period and 
that the investigator assesses as possibly related to the study intervention should also 
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• Is life-threatening. This refers to an event in which the subject was at risk of death at 
the time of the event. It does not include an event that, had it occurred in a more 
severe form, hypothetically might have caused death. 
• Requires hospitalization or prolongation of existing hospitalization (excluding 
hospitalizations for administration of the study intervention, procedures required by 
the study protocol, or treatment-related diagnostic procedures; other planned 
hospitalizations; or hospitalizations related only to progression of disease). 
Emergency room visits that do not require admission to the hospital do not fall into 
this category, but the event may still be serious due to another seriousness criterion. 
• Results in persistent or significant disability or incapacity or substantial disruption of 
the ability to conduct normal life functions. 
• Any other medically important event that the investigator or PTC judges to be serious 
or which is defined as serious by the regulatory agency in the local country. These are 
AEs that might not be immediately life-threatening or result in death or 
hospitalization but might jeopardize the subject or might require intervention to 
prevent one of the other outcomes listed above. Medical judgment should be 
exercised in deciding whether an AE is serious based on the above definition. 
Examples of such events are intensive treatment in an emergency room or at home for 
allergic bronchospasm, blood dyscrasias or convulsions that do not result in 
hospitalization, or development of drug dependency or drug abuse. 
A pregnancy resulting in spontaneous abortion, stillbirth, neonatal death, or congenital anomaly 
(including that in an aborted fetus). Note: Hospitalization for social circumstances without any 
other accompanying SAE should not be reported as an SAE. 
8.2.3. 
Adverse Events Reporting 
Adverse events will be reported by the subject. 
The investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible to pursue and 
obtain adequate information both to determine the outcome and to assess whether the event 
meets the criteria for classification as an SAE or caused the subject to discontinue the study 
intervention (see Section 4.4). 
Each subject will be questioned about the occurrence of AEs in a nonleading manner. 
In addition, the investigator may be requested by PTC Pharmacovigilance Department to obtain 
specific follow-up information in an expedited fashion. 
All AEs are to be recorded in the source documents and on the eCRF using concise medical 
terminology; whenever possible, terms contained in the Medical Dictionary for Regulatory 
Activities (MedDRA) should be employed. In addition, the following information should be 
recorded: 
• Indication of whether the event is serious or nonserious (see Section 8.2.2) 
• Relationship to study intervention (see Section 8.2.5) 
• Severity of the event (see Section 8.2.5) 

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• Onset date 
• Resolution date, or date of death 
• Action taken 
• Outcome of the event 
Table 6 summarizes the investigator site requirements for recording AEs on the eCRF and for 
reporting SAEs and adverse events of special interest on the SAE Report Form to PTC 
Pharmacovigilance Department. 
Table 6: 
Investigator Site Requirements for Recording/Reporting Adverse Events 
Event 
Recorded on the eCRF 
Reported to PTC Pharmacovigilance 
Within 24 Hours of Awareness 
Serious AE 
All 
All 
Nonserious AE 
All 
None 
AESI 
Not applicable 
Not applicable 
Other, eg, exposure during 
pregnancy or breastfeeding 
All (regardless of 
whether associated with 
an AE) 
All (regardless of whether associated 
with an AE) 
Abbreviations: AE, adverse event; AESI, adverse event of special interest; eCRF, electronic case report form 
8.2.4. 
Time Period and Frequency for Collecting/Reporting Adverse Event 
Information 
The AE (both serious and nonserious) collection and AE reporting period begins with the signing 
of the ICF and continues until 6 months after the last dose of study medication. All AEs during 
this time period must be recorded whether or not the event is considered drug related. 
For subjects who are screen failures, the active collection period for AEs ends when screen 
failure status is determined. Any SAEs occurring during screening procedures should be 
reported, and the appropriate causality assessment (ie, “not related” to study intervention) section 
of the SAE Report Form must be completed. 
If the subject withdraws from the study and also withdraws consent for the collection of future 
information, the active collection period for AEs ends when consent is withdrawn. 
Investigators are not obligated to actively seek information on AEs or SAEs after conclusion of 
the study participation. However, if the investigator learns of any SAE, including a death, at any 
time after a subject has been discharged from the study, and he/she considers the event to be 
reasonably related to the study intervention, the investigator must promptly notify PTC 
Pharmacovigilance Department via the SAE Report Form. 
8.2.4.1. 
Serious Adverse Event Reporting 
All SAEs (both initial and follow-up) must be reported via the SAE Report Form to 
PTC Pharmacovigilance Department immediately, and under no circumstance should this exceed 
24 hours from awareness. In addition, the AE portion of the eCRF must also be completed. 
The SAE Report Form must be signed by the investigator; however, if the investigator is unable 
to sign at the time of the event or within 24 hours, the form should be signed by the clinical staff 
member reporting the SAE (eg, the study coordinator). The SAE Report Form must be faxed or 
emailed to the PTC Pharmacovigilance Department and to the site Institutional Review 

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Board (IRB)/Independent Ethics Committee (IEC) (if required by local regulations) within 
24 hours. The investigator’s signature must be obtained as soon as possible after the report is 
submitted, and the report revised if necessary and submitted to PTC Pharmacovigilance 
Department. The investigator will maintain a copy of the SAE Report Form on file at the study 
site. 
Follow-up information to the SAE should be clearly documented as “follow-up” in the SAE 
Report Form and must also be faxed or emailed to the same party within the same timelines. All 
follow-up SAE Report Forms for the event must be signed by the investigator as per instructions 
above. Any source documents (eg, progress notes, nurses’ notes, laboratory and diagnostic test 
results, discharge summaries) provided to PTC should be redacted so that the subject’s name, 
address, and other personal identity information are obscured. Only the subject’s study number 
and initials are to be provided (in regions where the provision of such information is permitted). 
The information in the AE portion of the eCRF and the SAE Report Form(s) must match or be 
reconciled. Where the same data are collected, the forms must be completed in a consistent 
manner. For example, the same AE term should be used on both forms. 
The PTC Pharmacovigilance Department contact information for reporting SAEs is provided 
below. This information is also provided in the SAE Report Form. 
PTC Pharmacovigilance Department 
Email: Pharmacovigilance@ptcbio.com 
SAE Fax Line: +1-908-325-0355 
8.2.5. 
Method of Detecting Adverse Events and Serious Adverse Events 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
nonleading verbal questioning of the subject is the preferred method to inquire about AE 
occurrences. 
8.2.5.1. 
Assessment of Severity of Adverse Events 
The severity of AEs will be graded using the Common Terminology Criteria for Adverse 
Events (CTCAE) Version 5.0. For each episode, the highest severity grade attained should be 
reported. 
The investigator will make an assessment of severity for each AE and SAE reported during the 
study and assign it to one of the following categories (Table 7). 
Table 7: 
Grading of Adverse Events 
Grade 
Adjective 
Description 
1 
Mild 
Asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated 
2 
Moderate 
Minimal, local, or noninvasive intervention indicated, limiting age-
appropriate instrumental ADL. Instrumental ADL refers to preparing 
meals, shopping for groceries or clothes, using the telephone, 
managing money, etc. 
3 
Severe 
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling, 
limiting self-care ADL. Self-care ADL refers to bathing, dressing and 
undressing, feeding self, using the toilet, taking medications, and not 
bedridden. 

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Grade 
Adjective 
Description 
4 
Life-threatening 
Sign or symptom results in urgent intervention. 
5 
Fatal 
Sign or symptom results in death. 
Abbreviations: ADL, activities of daily living 
8.2.5.2. 
Describing Adverse Event Relationship to Study Intervention 
The investigator should provide an assessment of the relationship of the AE/SAE to the study 
intervention, and each occurrence of each AE/SAE as outlined in Table 8. The investigator will 
use clinical judgment to determine the relationship. 
The investigator will also consult the Investigator’s Brochure in his/her assessment. 
For each AE/SAE, the investigator must document in the medical notes that he/she has reviewed 
the AE/SAE and has provided an assessment of causality. 
There may be situations in which an AE/SAE has occurred, and the investigator has minimal 
information to include in the initial SAE Report Form to PTC Pharmacovigilance Department. 
However, it is very important that the investigator always make an assessment of causality for 
every event before the initial transmission of the SAE Report Form to PTC Pharmacovigilance 
Department. 
The investigator should decide whether, in his or her medical judgment, there is a reasonable 
possibility that the event may have been caused by the investigational product. 
• If no valid reason exists for suggesting a relationship, then the AE should be 
classified as “unrelated.” If a relationship cannot be excluded but there is a clear 
alternate cause that is more likely to have caused the AE than study intervention, the 
AE should be considered “unlikely related.” 
• If there is any valid reason, even if undetermined, for suspecting a possible 
cause-and-effect relationship between the investigational product and the occurrence 
of the AE, then the AE should be considered “possibly or probably related.” 
If the relationship between the AE/SAE and the investigational product is determined to be 
“possible” or “probable,” the event will be considered to be related to the investigational product 
or the purposes of expedited regulatory reporting. An assessment of “unlikely related” will be 
considered unrelated for regulatory reporting purposes. 
The investigator may change his/her opinion of causality in light of follow-up information and 
must send an SAE Follow-Up Report Form with the updated causality assessment. 
The causality assessment is one of the criteria used when determining regulatory reporting 
requirements (Table 8). 
Table 8: 
Relationship of Study Intervention to Adverse Event 
Relationship 
Description 
Probably 
A clinical event in which a relationship to the study intervention seems probable 
because of such factors as consistency with known effects of the drug; a clear 
temporal association with the use of the drug; improvement upon withdrawal of the 
drug; recurrence upon rechallenge with the drug; lack of alternative explanations for 
the event.  

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Relationship 
Description 
Possible 
A clinical event occurring coincident with administration of the study intervention, 
and which may or may not be explained by concurrent disease or other drugs or 
chemicals. Information on drug withdrawal or rechallenge may be lacking.  
Unlikely 
A clinical event with a temporal relationship to the study intervention exposure that 
does not preclude causality but for which there is a clear alternate cause that is 
more likely to have caused the adverse event than study intervention. Such 
alternatives include a concomitantly administered drug, the subject’s disease state, 
other medical conditions, or environmental factors.  
Unrelated 
A clinical event, for which a relationship to the study intervention seems improbable 
because of factors such as inconsistency with known effects of the study 
intervention, lack of a temporal association with study intervention administration, 
lack of association of the event with study intervention withdrawal or rechallenge, 
and/or presence of alternative explanations for the event. Alternative explanations 
might include a known relationship of the adverse event to a concomitant drug, 
medical history of a similar event, the subject’s disease state, other medical 
conditions, or environmental factors  
8.2.6. 
Follow-Up of Adverse Events and Serious Adverse Events 
After the initial AE/SAE Report Form, the investigator is required to proactively follow each 
subject at subsequent visits/contacts. All AEs will be followed until resolution, stabilization, the 
event is otherwise explained, or the subject is lost to follow-up (see Section 4.6). 
All AEs should be followed up by the investigator until they are resolved or the investigator 
assesses them as chronic or stable. The investigator should consider protocol guidelines and use 
his/her discretion in ordering additional tests as necessary to monitor the resolution of such 
events. In the event of additional investigations, PTC Pharmacovigilance should be informed via 
email or fax. 
A subject withdrawn from the study because of an AE must be followed by the investigator until 
clinical recovery is complete and laboratory results have returned to normal or until progression 
has been stabilized. Follow-up may need to continue after the subject has discontinued from the 
study, and additional investigations may be requested by the medical monitoring team. 
The investigator must submit any updated SAE information to PTC Pharmacovigilance 
Department within 24 hours of receipt of the information. 
8.2.7. 
Regulatory Reporting Requirements for Serious Adverse Events 
Prompt notification by the investigator to PTC of an SAE is essential so that legal obligations 
and ethical responsibilities toward the safety of subjects and the safety of a study intervention 
under clinical investigation are met. 
As the sponsor of the study, PTC has a legal responsibility to notify both the local regulatory 
authority and other regulatory agencies about the safety of a study intervention under clinical 
investigation. PTC will comply with country-specific regulatory requirements relating to safety 
reporting to the regulatory authority, IRBs/IECs, and investigators. 
Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions (SUSARs) according to local regulatory requirements and PTC policy and forwarded to 
investigators as necessary. 

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An investigator who receives SUSAR report(s) or other safety specific information (eg, summary 
or listing of SAEs) from PTC will review and then file it along with the reference safety 
information (Investigator’s Brochure) and will notify the IRB/IEC, if appropriate, according to 
local requirements. 
8.2.8. 
Exposure During Pregnancy or Breastfeeding 
Exposure to the study intervention under study during pregnancy or breastfeeding are reportable 
to PTC Pharmacovigilance within 24 hours of investigator’s awareness. 
8.2.8.1. 
Exposure During Pregnancy 
PTC Pharmacovigilance must be notified in the event that a female subject in the study, or a 
female partner of a male subject in the study, becomes pregnant on-study or within 6 months of 
the last dose of the study medication on an Investigational and Marketed Products Pregnancy 
Report Form (hereafter referred to as Pregnancy Report Form; refer to the study manual for 
details). This must be reported whether or not an AE has occurred and within 24 hours of 
awareness of the pregnancy. The information submitted should include the anticipated date of 
birth or pregnancy termination. 
Written consent is required prior to collecting and reporting any information on a female partner 
of a male subject in the study. 
In any of the 4 situations listed below, the subject will be provided with a Pregnancy/Pregnant 
Partner Data Release Form to request their consent to follow the progress of the pregnancy and 
the birth and the health of their child. 
• Subject becomes pregnant while participating in the study. 
• Female partner of a male subject in the study becomes pregnant. 
• Subject becomes pregnant up to 6 months after completion of the study. 
• Female partner of a male subject in the study becomes pregnant up to 6 months after 
the partner completed the study. 
Because the risk to an unborn child is unknown, the subject should be asked to sign the 
Pregnancy/Pregnant Partner Release Form. However, signing this form is voluntary; it is up to 
the subjects to decide whether to agree to the collection of this information or not. Upon signing, 
the subject’s and the child’s medical records relating to the pregnancy and delivery, and the 
health of the child, will be reviewed for up to 1 year of age. 
If possible, the investigator should follow the subject, or the pregnant female partner of a male 
subject, until completion of the pregnancy and notify the medical monitor of the outcome within 
5 days or as specified below. The investigator must provide this information as a follow-up to the 
initial Pregnancy Report Form via the Pregnancy Outcome Section (refer to the study manual for 
details). 
If the outcome of the pregnancy meets the criteria for immediate classification as an SAE 
(ie, spontaneous abortion, stillbirth, neonatal death, or congenital anomaly [including that in an 
aborted fetus]), the investigator should follow the procedures for reporting SAEs (ie, report the 
event to PTC Pharmacovigilance Department and follow up by completion of appropriate AE 
eCRFs and submission of the SAE Report Form). 

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All information collected with regard to the pregnancy, the delivery of the child, and the health 
of the child is confidential to the limit allowed by law. These data will be coded to hide the 
subject’s identity and the identity of the child. In particular, the subject’s name and the child’s 
name will not be reproduced on any other paper or electronic document. These data will not be 
disclosed voluntarily by PTC. However, regulatory agencies may have to examine these data to 
ensure that the study is done properly. 
Of note, if the pregnant female partner of a male subject participating in the study does not wish 
to provide such information, this will not prevent the partner from continuing with the study. 
Any female subject who becomes pregnant while participating in the study will discontinue 
study intervention or be withdrawn from the study (see Section 4.4). 
8.2.8.2. 
Exposure During Breastfeeding 
An exposure during breastfeeding occurs if: 
• A female subject is found to be breastfeeding while receiving or after discontinuing 
study intervention. 
• A female is found to be breastfeeding while being exposed or having been exposed to 
study intervention (ie, environmental exposure). An example of environmental 
exposure during breastfeeding is a female family member or healthcare provider who 
reports that she is breastfeeding after having been exposed to the study intervention 
by inhalation or skin contact. 
The investigator must report exposure during breastfeeding to PTC Pharmacovigilance 
Department within 24 hours of the investigator’s awareness, irrespective of whether an SAE has 
occurred. The information must be reported using the Investigational and Marketed Products 
Pregnancy Report Form. When exposure during breastfeeding occurs in the setting of 
environmental exposure, the exposure information does not pertain to the subject enrolled in the 
study, so the information is not recorded on an eCRF. However, a copy of the completed 
Investigational and Marketed Products Pregnancy Report Form is maintained in the investigator 
site file. An exposure during breastfeeding report is not created when a PTC drug specifically 
approved for use in breastfeeding women (eg, vitamins) is administered in accordance with 
authorized use. However, if the infant experiences an SAE associated with such a drug, the SAE 
is reported together with the exposure during breastfeeding via SAE Report Form. 
8.2.9. 
Cardiovascular and Death Events 
No cardiovascular or death events have been observed in clinical studies with PTC518. 
8.2.10. 
Disease-Related Events and/or Disease-Related Outcomes Not Qualifying as 
Adverse Events or Serious Adverse Events 
8.2.10.1. Progression of Underlying Disease 
If the progression of the underlying disease is greater than that which would normally be 
expected, or if the investigator considers that there may be a causal relationship between the 
study drug or protocol design/procedures and the disease progression, and meets the seriousness 

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criteria, then it must be reported to PTC Pharmacovigilance Department within 24 hours of 
awareness. 
8.2.10.2. Abnormal Findings Associated With the Disease Being Studied 
Clinically significant abnormal laboratory findings or other abnormal assessments that are 
detected during the study or are present at baseline of this study and significantly worsen 
following the start of the study will be reported as AEs or SAEs. However, clinically significant 
abnormal laboratory findings or other abnormal assessments that are associated with the disease 
being studied, unless judged by the investigator as more severe than expected for the subject’s 
condition, or that are present or detected at the start of the study and do not worsen, should not 
be reported as AEs or SAEs. 
8.2.11. 
Contraceptive Guidance 
8.2.11.1. Male Subject Reproductive Inclusion Criteria 
Male subjects are eligible to participate if they agree to the following requirements during the 
treatment period and for at least 6 months after the last dose of study intervention, which 
corresponds to the time needed to eliminate reproductive safety risk of the study intervention(s): 
• Refrain from donating sperm. 
PLUS, either: 
• Be abstinent from heterosexual intercourse with a female of childbearing potential as 
their preferred and usual lifestyle (abstinent on a long-term and persistent basis) and 
agree to remain abstinent. 
OR 
• Must agree to use a male condom when engaging in any activity that allows for 
passage of ejaculate to another person. 
• In addition to male condom use, a highly effective method of contraception may be 
considered in WOCBP partners of male subjects (refer to the list of highly effective 
methods in Section 8.2.11.4). 
8.2.11.2. Female Subject Reproductive Inclusion Criteria 
A female subject is eligible to participate if she is not pregnant or breastfeeding, and at least one 
of the following conditions applies: 
• Is not a WOCBP (per definition in Section 8.2.11.3). 
OR 
• Is a WOCBP and using an acceptable contraceptive method as described in 
Section 8.2.11.4 during the intervention period and for a minimum of 6 months after 
the last dose of study intervention. The investigator should evaluate the effectiveness 
of the contraceptive method in relationship to the first dose of study intervention. The 
investigator is responsible for review of medical history, menstrual history, and recent 

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sexual activity to decrease the risk for inclusion of a woman with an early undetected 
pregnancy. 
8.2.11.3. Women of Childbearing Potential 
Women of childbearing potential are defined as women who are fertile following menarche and 
until becoming postmenopausal unless permanently sterile. Permanent sterilization methods 
include hysterectomy, bilateral salpingectomy, and bilateral oophorectomy. 
Postmenopausal is defined as no menses ≥12 months without an alternative medical cause. In 
addition, a high FSH level in the postmenopausal range must be used to confirm a 
postmenopausal state in women not using hormonal contraception or hormone replacement 
therapy. However, in the absence of 12 months of amenorrhea, a single FSH measurement is 
insufficient. 
8.2.11.4. 
Contraception Methods 
Contraceptive use by men or women should be consistent with local availability/regulations 
regarding the use of contraceptive methods for those participating in clinical trials. 
Women of childbearing potential must agree to use highly effective methods of contraception 
during dosing and for 6 months after stopping the study medication. 
Female partners of enrolled males who are of childbearing potential should consider use of 
highly effective methods of contraception while the enrolled male is taking study drug and for 
6 months after stopping study drug. 
Highly effective contraception methods are defined as those that can achieve a failure rate of less 
than 1% per year when used consistently and correctly and include the following: 
• Combined (estrogen and progestogen containing) hormonal contraception associated 
with inhibition of ovulation: 
− Oral 
− Intravaginal 
− Transdermal 
• Progestogen-only hormonal contraception associated with inhibition of ovulation: 
− Oral 
− Injectable 
− Implantable 
• Intrauterine device 
• Intrauterine hormone-releasing system 
• Bilateral tubal occlusion 
• Vasectomized partner 
• Sexual abstinence 

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In case of use of oral contraception, WOCBP should have been stable on the same pill for a 
minimum of 3 months prior to Screening. 
Abstinence is acceptable only as true abstinence when this is in line with the preferred and usual 
lifestyle of the subject. Periodic abstinence (eg, calendar, ovulation, symptothermal, 
post-ovulation methods) and withdrawal are not acceptable methods of contraception. 
8.2.12. 
Adverse Events of Special Interest 
Not Applicable 
8.2.13. 
Medication Errors 
Table 9 shows the requirements for reporting medication errors. 
Table 9: 
Investigator Site Requirements for Recording/Reporting Medication Errors 
Event 
Recorded on the eCRF 
Reported to PTC Pharmacovigilance 
Within 24 Hours of Awareness 
Medication errors 
All (regardless of whether associated 
with an AE) 
Only if associated with an SAE 
Abbreviations: AE, adverse event; eCRF, electronic case report form; SAE, serious adverse event 
Medication errors include the following: 
• Potential medication errors or uses outside of what is foreseen in the protocol that do 
or do not involve the study subject 
• Administration of expired study intervention 
• Administration of an incorrect dosage 
• Administration of study intervention that has undergone temperature excursion from 
the specified storage range, unless it is determined by PTC that the study intervention 
under question is acceptable for use. 
Such medication errors occurring to a study subject are to be captured in source documents and 
in the eCRF as applicable. 
Whether or not the medication error is accompanied by an AE, as determined by the investigator, 
the medication error is recorded in source documents, and if applicable, any associated AEs, 
serious and nonserious, are recorded on the AE page of the eCRF. 
If a medication error is associated with an SAE, this must be reported to PTC Pharmacovigilance 
Department within 24 hours of awareness on the SAE Report Form. 
 

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9. 
STATISTICS 
This section outlines the statistical and analytical methods to be used in the study. Exploratory 
analyses of the data not described in the following subsections may be conducted as deemed 
appropriate. Additional details will be provided in the statistical analysis plan (SAP), which will 
be finalized before study unblinding. 
9.1. 
Subject Populations for Analysis 
Intent-to-Treat (ITT) Population: All randomized subjects who take at least 1 dose of study 
drug. The ITT Population will be used in all efficacy analysis and subjects will be analyzed 
according to their randomized treatment. 
Per Protocol (PP) Population: All subjects in the ITT population who have no major protocol 
deviations that affect the validity of the efficacy measurements. The PP Population will be used 
for sensitivity analysis of the efficacy endpoint. The criteria for inclusion in the PP Analysis Set 
will be finalized prior to study unblinding and detailed in the SAP. 
Safety Population: All randomized subjects who receive at least 1 dose of study drug, with 
subjects grouped according to the treatment they actually receive. The Safety Population will be 
used in all safety analyses. 
PK Population: All randomized subjects who take at least 1 dose of study drug. This analysis 
set comprises all subjects included in the Safety Population who did not violate the protocol in a 
way that might affect the evaluation of the effect of the study drug(s) on the PK assessment 
(ie, without major protocol violations or deviations). 
9.2. 
Sample Size Determination 
The sample size calculation for each disease stage is based on mean change from Baseline in 
blood tHTT protein at Month 3 (primary endpoint), assuming PTC518 has the same effect on 
blood tHTT protein reduction. With an effect size of 0.85 (ie, the magnitude of treatment 
difference is 85% of one standard deviation), achievement of 85% power at 2-sided alpha level 
0.05 would require 24 subjects. Approximately 24 subjects will be randomized to each active 
treatment arm and approximately an additional 36 subjects per disease stage will be randomized 
to placebo. An additional 18 subjects (per disease stage) may be randomized to the maximum 
tolerated dose. Up to 252 adult male and female subjects (126 per disease stage) will be enrolled. 
9.3. 
Statistical Methods 
9.3.1. 
General Approach 
Summary tables for continuous variables will contain the following statistics: N, mean, median, 
standard deviation, standard error, minimum, maximum, and 95% confidence intervals as 
appropriate. Summary tables for categorical variables will include N and percentage in each 
category. Graphical techniques will be used when such methods are appropriate and informative. 
By-subject listings will be created. 
Endpoints will be evaluated primarily with both disease stages combined, and by disease stage. 
Transformations of the data may be explored if warranted by the distribution of the data. 

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9.3.2. 
Safety Analyses 
The safety analysis will be performed for the Safety Population. Descriptive statistics of safety 
will be presented using National Cancer Institute (NCI) CTCAE by treatment group. All TEAEs 
will be tabulated by System Organ Class and MedDRA Preferred Term. On-study laboratory 
abnormalities including hematology and chemistry will be summarized using worst grade per 
NCI CTCAE criteria. 
9.3.2.1. 
Adverse Events 
AEs will be tabulated using the MedDRA classification system. The frequency of subjects 
experiencing a specific AE will be tabulated by treatment group, System Organ Class, Preferred 
Term, seriousness (nonserious versus serious), worst severity, outcome, and relationship to study 
drug. Subject with AEs leading to death or to discontinuation from treatment, and SAEs will be 
listed. 
9.3.2.2. 
Laboratory Abnormalities 
The severity of laboratory abnormalities will be graded using the CTCAE whenever possible. 
The frequency of subjects experiencing a specific laboratory abnormality will be tabulated by 
treatment group and worst severity. In addition, the number and percentage of subjects 
experiencing a specific laboratory abnormality will be tabulated similarly. 
9.3.2.3. 
Other Safety Assessments 
The results of vital sign measurements, body weight assessments, and ECG assessments will be 
summarized by treatment group by using appropriate descriptive statistics. 
9.3.3. 
Efficacy Analyses 
9.3.3.1. 
Analysis of the Primary Efficacy Endpoint 
The primary efficacy endpoint is change from baseline in blood tHHT protein at Month 3. The 
null hypothesis of this study is that the mean change from Baseline for blood tHTT protein is the 
same in the PTC518 arm and in the placebo arm versus the alternative that they are different. 
A repeated measure analysis model (repeat on visit) will be used to compare each dose with 
placebo for blood tHTT protein levels. The model will include treatment, visit, treatment by-visit 
interaction and baseline blood tHTT, CAG, age, and CAG by age interaction as covariates. 
Nominal p values and 95% confidence interval for each pairwise comparison at Month 3 (active 
vs placebo) will be provided. The model will include disease stage (by PINHD bin for Stage 2 
only and by TFC for Mild Stage 3 only) as a stratification factor. 
For Stage 2, PINHD will be used as a stratification factor with the following stratification classes: 
• 0.180 to 0.679 
• 0.680 to 1.520 
• 1.521 to 4.930 

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For Mild Stage 3, TFC will be used as stratification factors with the following stratification 
classes: 
• 11 
• 12 
• 13 
9.3.3.2. 
Analysis of Secondary Endpoints 
The key secondary endpoint (change from baseline in caudate volume as assessed via vMRI at 
Month 12) will be analyzed by a mixed model repeated measures (MMRM) model using all 
available vMRI data up to the Month 12 Visit. The model will include fixed effects for treatment, 
baseline vMRI, and disease stage (by PINHD bin for Stage 2 only and by TFC for Mild Stage 3 
only). The intercept and time of collection will be included as a random effect nested within 
subjects. The unstructured covariance matrix will be used in the model. The rate of changes will 
be compared between treatments and the least squares (LS) mean differences at Month 12 will 
also be provided. 
For change from baseline in cUHDRS, a MMRM analysis (repeat at visit) will be performed 
using all data collected up to 12 months. The model will use treatment group, visits (categorical), 
treatment by-visit interaction, disease stage as fixed factors, CAG, age, and CAG by age 
interaction as covariates. The LS mean estimates for the change from Month 12, the difference 
between pairwise comparison with placebo, confidence intervals, and 2-sided p value will be 
presented. A similar model will be used for UHDRS sub-scores and PBA-s. Rate of changes in 
these scores will also be explored. 
For by disease stage analyses, PINHD category (0.180 to 0.679, 0.680 to 1.520, or 1.521 to 4.930) 
will be used as a fixed factor for Stage 2 only, and TFC score (11, 12, or 13) will be used as a 
fixed factor for Mild Stage 3 only. 
A repeated measure analysis model, similar to the analysis model used for blood tHTT protein, 
will be used for blood and CSF mHTT protein. Dose-response relationships will be explored and 
a by-visit summary of blood tHTT and blood and CSF mHTT protein will be displayed. 
An analysis of covariance model with dose and Baseline in the model will be used to analyze 
change from Baseline to Month 12 in mHTT protein (in blood and CSF). Nominal p values and 
95% confidence interval for each pairwise comparison will be calculated. 
9.3.3.3. 
Analysis of Exploratory Endpoints 
Change from Baseline in CSF mHTT protein and in blood mHTT protein at Month 3 will be 
summarized descriptively. 
Change from Baseline in imaging parameters whole brain, putamen, and ventricular volume (as 
assessed by vMRI) will be summarized descriptively. 
Change from Baseline in PBA-s, and UHDRS sub-scores, including TFC, TMS, SDMT, and IS, 
will be summarized descriptively. The relation between these parameters with blood HTT 
protein will be explored. 
Change from Baseline in the FuRST 2.0 questionnaire will be summarized descriptively. 

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Change over time in blood HTT mRNA will be summarized descriptively. 
Change over time in concentrations of NfL protein (in plasma and CSF) and 
 
will be summarized descriptively. 
Change from Baseline in wearable accelerometer assessment TUG, 2-minute walk distance, and 
postural sway will be summarized descriptively. 
9.3.4. 
Analysis of Pharmacokinetic Endpoints 
Individual and descriptive plasma concentration at predose and postdose will be reported for 
each visit. Individual and descriptive accumulation of study drug will be calculated and reported 
for both plasma and CSF using predose concentrations at Visits 3 through 8 for plasma and at 
Visits 5 through 8 for CSF, respectively. 
9.3.5. 
Baseline Descriptive Statistics 
9.3.5.1. 
Disposition 
Subjects who did not complete the treatment or study will be summarized. Reasons for 
treatment/study discontinuation will be summarized. 
9.3.5.2. 
Demographics and Baseline Characteristics 
Subject demographics and baseline characteristics at study entry will be summarized with 
frequency tables for categorical variables and descriptive statistics such as the mean, standard 
deviation, median, and range, as appropriate, for quantitative variables. 
9.3.5.3. 
Medical History and Prior Medication 
Medical history and prior medication information will be summarized by treatment group. 
9.3.6. 
Extent of Exposure and Concomitant Medications 
Exposure to study drug will be summarized descriptively by treatment group. 
Concomitant medication information will be summarized by treatment group. 
9.4. 
Planned Interim Analyses 
PTC plans to conduct an interim analysis to confirm the PK and PD expectations and to evaluate 
safety when approximately 36 subjects from the 5 mg dosing group (Parts A and/or D), and 36 
subjects from the 10 mg dosing group (Parts B and/or E), including placebo, have completed 12 
weeks of treatment. An independent analysis team will conduct the unblinded analysis. Only 
summary level results will be shared with the PTC study team. The study will maintain double-
blinding for investigators and the sponsor study team at a subject level until after the database is 
locked. More details will be provided in an interim SAP. 
9.5. 
Statistical Significance 
The significance level will be 0.05, using 2-sided tests for the primary efficacy endpoint. 

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9.6. 
Missing Data 
Missing data will not be imputed for summaries for all safety endpoints and for by-visit 
summaries for all the PD parameters including tHTT protein (in blood). 
For the primary analysis of the primary endpoint, MMRM model will be used on the available 
data assuming the missing assessments are missing at random. Missing data will be imputed 
using the multiple imputation procedure (Rubin 1987, Ouyang 2017) to further assess the 
influence of missing primary endpoint data and details of the method will be provided in the 
SAP. Briefly, these methodologies will include multiple imputation under an assumption of 
missing not at random and tipping-point analyses to explore how extreme the difference between 
randomized treatments would have to be among subjects with missing data to overwhelm the 
treatment effect obtained in the primary. In these analyses, the multiple imputation approach will 
be expanded to allow for varying impact of missing data by incorporating a shift parameter in the 
imputation model. The range of values for the shift parameter will explore the varying missing 
data assumptions, including the scenario where the imputation model is completely based on the 
control group (ie, control-based imputation). 
More details of missing data handling will be provided in the SAP. 

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10. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
In accordance with 21 Code of Federal Regulations Part 312.56 and/or relevant ICH guidelines, 
PTC or a designee will periodically inspect all eCRFs, study documents, research facilities, and 
clinical laboratory facilities associated with this study at mutually convenient times, before, 
during, and after completion of the study. As required by applicable regulations (FDA 2020), the 
monitoring visits provide PTC with the opportunity to evaluate the progress of the study; verify 
the accuracy and completeness of data in the eCRFs; ensure that all protocol requirements, 
relevant regulations, and investigator’s obligations are being fulfilled; and resolve any 
inconsistencies in the study records. This includes inspection of all documents and records 
required to be maintained by the investigator, including but not limited to medical records 
(office, clinic, or hospital) for the subjects in this study. The names and identities of all research 
subjects will be kept in strict confidence and will not appear on eCRFs or other records provided 
to or retained by PTC. The investigator/institution guarantees direct access to source documents 
by PTC or a designee and appropriate regulatory authorities. 
It is important that the investigator and relevant institutional personnel are available during the 
monitoring visits and possible audits or inspections and that sufficient time is devoted to the 
process. 
10.1. 
Study Monitoring 
Before a potential investigational site can be selected to conduct the study, a representative of 
PTC or its designee will visit the investigational study site to: 
• Determine the adequacy of the facilities 
• Discuss with the investigator(s) and other personnel their responsibilities with regard 
to protocol adherence, and the responsibilities of PTC or its representatives. This will 
be documented in a Clinical Study Agreement between PTC and the investigator. 
During the study, a monitor from PTC or representative will have regular contacts with the 
investigational site, for the following: 
• Provide information and support to the investigator(s). 
• Confirm that facilities remain acceptable. 
• Confirm that the investigational team is adhering to the protocol, that data are being 
accurately recorded in the case report forms, and that investigational product 
accountability checks are being performed. 
• Perform source data verification. This includes a comparison of the data in the case 
report forms with the patient’s medical records at the hospital or practice, and other 
records relevant to the study. This will require direct access to all original records for 
each patient (eg, clinic charts). 
• Record and report any protocol deviations not previously sent to PTC. 
• Confirm AEs and SAEs have been properly documented on eCRFs and confirm any 
SAEs have been forwarded to PTC and those SAEs that met criteria for reporting 
have been forwarded to the IRB/IEC. 

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The monitor will be available between visits if the investigator(s) or other staff needs 
information or advice. 
10.2. 
Audits and Inspections 
PTC may conduct audits of clinical research activities in accordance with internal SOPs to 
evaluate compliance with the principles of Good Clinical Practice (GCP) and ICH related 
guidelines. 
Health Authorities may also wish to conduct an inspection (during the study or after its 
completion). Should an inspection be requested by Health Authorities, the investigator must 
inform PTC immediately that such request has been made. 
The investigator will permit such audits by PTC or Health Authorities and facilitate them by 
providing access to the relevant source documents. 
10.3. 
Safety Oversight 
External oversight for this study will be provided by a DSMB as defined in the DSMB Charter. 
The primary responsibility of the DSMB is to protect the safety and welfare of subjects 
participating in this clinical study and to ensure the integrity of the clinical study. To maintain 
the blinding and integrity of the study, procedures will be implemented to ensure that the DSMB 
and independent statistician have sole access to unblinded safety data. 
Specifically, for this study, the DSMB will be responsible for the following: 
• Examining accumulated safety data, PK, PD, biomarker, and compliance data in 
order to make recommendations concerning continuation, termination, or 
modification of the study based on the safety of the interventions under study 
• Reviewing major study design modifications proposed by PTC or the investigators 
prior to implementation of those modifications 
• Reviewing the general progress of the study as regards accrual, protocol violations, 
and study conduct 

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11. 
QUALITY CONTROL AND QUALITY ASSURANCE 
To ensure compliance with GCP and all applicable regulatory requirements, PTC, 
PTC’s representatives, a regulatory authority, IEC, and/or IRB may conduct a quality assurance 
audit. Reasons for quality assurance audit may include, but are not limited to, random selection, 
geographic proximity, suspected GCP violation, high enrolling site, recurring protocol 
deviations, etc. The purpose of an audit or inspection by PTC is to systematically and 
independently examine all study-related activities and documents to determine whether these 
activities were conducted, and data were recorded, analyzed, and accurately reported according 
to the protocol, GCP guidelines of the ICH, and any applicable regulatory requirements. The 
investigator should contact PTC immediately if contacted by a regulatory agency about an 
inspection. 
11.1. 
Protocol Deviations 
A protocol deviation is defined as any intentional or unintentional change to, or noncompliance 
with, the approved protocol procedures or requirements. Deviations may result from the action or 
inaction of the subject, investigator, or site staff. Examples of deviations include, but are not 
limited to, the following: 
• Failure to adhere to study exclusion and inclusion criteria 
• Failure to comply with dispensing or dosing requirements 
• Use of medications that are specifically prohibited in the protocol 
• Missed or out-of-window visits 
• Drug dosing not administered within the time frame specified in the protocol 
• Failure to adhere to test requirements, including vital signs, laboratory tests, physical 
examinations, PK blood draws, medical history, etc (either the tests were not done, 
the incorrect tests were done, or the tests were not done within the time frame 
specified in the protocol) 
• Procedural deviations such as incorrect storage of study drug, failure to update the 
ICF when new risks become known, or failure to obtain IRB/IEC approvals for the 
protocol and ICF revisions 
Major deviations are any deviations that impact subject eligibility (ie, protocol 
inclusion/exclusion violations), subject safety, or a subject’s ability to continue in the study. 
At the outset of the study, a process for defining and handling protocol deviations will be 
established with the Contract Research Organization (CRO). This will include determining 
which deviations will be designated major; thus, requiring immediate notification to the medical 
monitor and PTC. Prospective deviations (eg, protocol waivers) are prohibited by PTC policy. 
The investigator is responsible for seeing that any known protocol deviations are recorded as 
agreed. 

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12. 
ETHICS 
12.1. 
Ethics Review 
The Principal Investigator must obtain IRB/IEC approval for the investigation. Initial IRB/IEC 
approval, and all materials approved by the IRB/IEC for this study including the patient consent 
form and recruitment materials must be maintained by the investigator and made available for 
inspection. 
The final study protocol, including the final version of the ICF, must be approved or given a 
favorable opinion in writing by an IRB or IEC as appropriate. The investigator must submit 
written approval to PTC before he or she can enroll any subject into the study. 
The Principal Investigator is responsible for informing the IRB or IEC of any amendment to the 
protocol in accordance with local requirements. In addition, the IRB or IEC must approve all 
advertising used to recruit patients for the study. The protocol must be re-approved by the IRB or 
IEC upon receipt of amendments and annually, as local regulations require. 
The Principal Investigator is also responsible for providing the IRB or IEC with reports of any 
reportable serious adverse drug reactions from any other study conducted with the investigational 
product. PTC will provide this information to the Principal Investigator. 
Progress reports and notifications of serious adverse drug reactions will be provided to the IRB 
or IEC according to local regulations and guidelines. 
12.2. 
Ethical Conduct of the Study 
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki and are consistent with ICH/GCP and applicable regulatory 
requirements. 
12.3. 
Written Informed Consent 
By signing the protocol, the investigator assures that informed consent will be obtained from 
each subject/subject’s caregiver prior to study entry and that the informed consent will be 
obtained in accordance with current regulations. 
The investigator or sub-investigator will give each subject full and adequate verbal and written 
information regarding the objectives and procedures of the study and the possible risks involved. 
An informed consent document will be provided to each subject in a language in which they are 
fluent. This information must be provided to the subject prior to undertaking any study-related 
procedure. Adequate time should be provided for the subject to read the informed consent, to 
understand the risks and benefits of participating in the study, and to ask any questions that the 
subject may have about the study. The subject’s signature on the ICF should be obtained at the 
investigator site in the presence of the investigator or a qualified representative 
(eg, sub-investigator). 
The original signed ICFs will be retained by the investigator with the study records. The written 
subject information must not be changed without prior approval by PTC and the IRB/IEC. 
The ICF will contain a separate section that addresses the use of remaining mandatory samples 
for optional exploratory research. The investigator or authorized designee will explain to each 
subject the objectives of the exploratory research. Subjects will be told that they are free to 

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refuse to participate and may withdraw their consent at any time and for any reason during the 
storage period. A separate signature will be required to document a subject’s agreement or 
refusal to allow any remaining specimens to be used for exploratory research. 

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13. 
DATA HANDLING AND RECORDKEEPING 
To enable evaluations and/or audits from regulatory authorities or PTC, the investigator agrees to 
keep accurate and complete records, including the identity of all participating subjects (sufficient 
information to link eCRFs and clinic records/source documents), all original signed ICFs, 
electronic copies (ie, CD-ROM, USB, etc) or paper copies of the data that have been captured in 
the EDC for each subject (eCRFs), and detailed records of study drug disposition. 
The investigator agrees to keep all information provided by PTC in strict confidence and to 
request similar confidentiality from his/her staff and the IRB/IEC. Study documents provided by 
PTC will be stored appropriately to ensure their confidentiality. The information provided by 
PTC to the investigator may not be disclosed to others without direct written authorization from 
PTC, except to the extent necessary to obtain informed consent from subjects who wish to 
participate in the study. 
All records and documents pertaining to the study will be maintained by the investigator until 
notification is received from PTC that the records no longer need to be retained. The investigator 
must obtain written permission from PTC before disposing of any records. The investigator will 
promptly notify PTC in the event of accidental loss or destruction of any study records. If the 
investigator relocates, retires, or for any reason withdraws from the study, the study records may 
be transferred to an acceptable designee, such as another investigator, another institution, or to 
PTC as applicable. 
13.1. 
Inspection of Records 
PTC will be allowed to conduct site visits to the investigation facilities for the purpose of 
monitoring any aspect of the study. The investigator agrees to allow the monitor to inspect the 
drug storage area, study drug stocks, Drug Accountability Records, subject charts and study 
source documents, and other records relative to study conduct. 
13.2. 
Retention of Records 
The investigator will maintain adequate and accurate records to enable the conduct of the study 
to be fully documented and the study data to be subsequently verified. These documents will be 
classified into 2 different categories: investigator’s file, and subject clinical source documents. 
The investigator’s file will contain the protocol/amendments, eCRFs, IEC/IRB and Health 
Authority approval with correspondence, informed consent, drug records, staff curriculum vitae 
and authorization forms, screening and enrollment logs, and other appropriate 
documents/correspondence as per ICH/GCP and local regulations. 
Subject clinical source documents include, but are not limited to subject hospital/clinic records, 
physician’s and nurse’s notes, appointment book, original laboratory, ECG, pathology and 
special assessment reports, consultant letters, etc. 
These 2 categories of documents must be kept on file by the investigator for as long as needed to 
comply with national and international regulations (generally 2 years after discontinuing clinical 
development or after the last marketing approval or 25 years, whichever is longest). No study 
document should be destroyed without prior written approval from PTC. Should the investigator 
wish to assign the study records to another party, or move them to another location, PTC must be 
notified in advance. 

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When source documents are required for the continued care of the subject, appropriate copies 
should be made for storing outside of the site. 
The handling of personal data will comply with local regulations. 
13.3. 
Future Use of Stored Specimens and Data 
As part of the current study, blood, plasma, urine, and CSF will be collected. Sample processing 
will be performed by a laboratory under the direction of PTC. Processing, analysis, and storage 
will be performed at a secure laboratory facility to protect the validity of the data and maintain 
subject privacy. Samples will only be used for the purposes described in this protocol. 
Laboratories contracted to perform the analysis on behalf of PTC will not retain rights to the 
samples beyond those necessary to perform the specified analysis and will not transfer or sell 
those samples. PTC will not sell the samples to a third party. 
PTC may store blood and CSF samples for up to 5 years after the end of the study, in accordance 
with local regulations, to achieve study objectives. Additionally, with subjects’ consent, samples 
may be used for further research by PTC to contribute to the understanding of HD. A separate 
section of the ICF will address the use of remaining samples for optional exploratory research, as 
described in Section 12.3. 
• Further research may include mutant HTT quantification in the CSF using a more 
sensitive and robust assay, if one is developed in the future. 
• If more robust longitudinal and cross-sectional data are available on the following 
biomarkers, they may be evaluated: 
At the end of the storage period, samples will be destroyed. Samples may be stored longer if a 
health authority (or medicinal product approval agency) has active questions about the study. In 
this special circumstance, the samples will be stored until the questions have been adequately 
addressed. No subject-identifying information (eg, initials, date of birth, government identifying 
number) will be associated with any of the biologic samples. All samples will be single coded. 
PTC will take steps to ensure that data are protected accordingly, and confidentiality is 
maintained as far as possible. 
Data from subjects enrolled in this study may be analyzed worldwide, regardless of location of 
collection. PTC and its representatives and agents may share coded data with persons and 
organizations involved in the conduct or oversight of this research. These include the following: 
• CROs retained by PTC 
• IECs or IRBs that have responsibility for this research study 
• National regulatory authorities or equivalent government agencies 
At the end of the analysis, results may be presented in a final report which can include part or all 
of the coded data, in listing or summary format. Other publication (eg, in peer-reviewed 
scientific journals) or public presentation of the study results will only include summaries of the 
population in the study, and no identified individual results will be disclosed. Given the research 
nature of the laboratory analysis, it will not be possible to return individual data to subjects. The 

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results that may be generated are not currently anticipated to have clinical relevance to the 
patients or their family members. Therefore, these results will not be disclosed to the patients or 
their physicians. 
13.4. 
Data Protection 
• Each clinical study subject will receive a unique identifier that is assigned to them via 
a web-integrated IRT system. Unique identifiers do not contain any personally 
identifiable information. Any subject records or datasets that are transferred or 
accessible to PTC will contain the unique identifier only. Directly identifiable 
personal information will not be transferred or accessible to PTC. 
• In the implementation of the study, PTC and the investigator will comply with all 
applicable privacy and data protection laws and any additional requirements as may 
be requested by the local data protection authorities (such as the CNIL Methodology 
MR001 in France) in order to perform the study. 
• The subject will be informed of the purposes and conditions under which his/her 
personal study-related data will be used by PTC in accordance with local data 
protection law. 
• The subject will be informed that his/her medical records related to the study may be 
examined by Clinical Quality Assurance auditors or other authorized personnel 
appointed by PTC to monitor the study, or by appropriate IRB/IEC members, or by 
inspectors from other regulatory authorities, as applicable under the local regulatory 
framework. 

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14. 
PUBLICATION POLICY 
The information developed during the conduct of this clinical study is considered confidential by 
PTC. This information may be disclosed as deemed necessary by PTC. 
PTC intends that the data from this study will be presented and published. The PTC staff under 
the direction of the PTC Chief Development Officer or designee in collaboration with the 
investigator will be responsible for writing presentations and manuscripts for publication. 
Investigators will not be allowed to publish or present the data from this study without prior 
agreement with PTC. 
The investigator is obliged to provide PTC with complete test results and all data derived by the 
investigator from the study. During the study, only PTC may make study information available 
to other study investigators or to regulatory agencies, except as required by law or regulation. 
Except as otherwise allowable in the Clinical Study Site Agreement, any public disclosure 
(including publicly accessible websites) related to the protocol or study results, other than study 
recruitment materials and/or advertisements, is the sole responsibility of PTC. 
PTC may publish any data and information from the study (including data and information 
generated by the investigator) jointly with the investigator. Manuscript authorship for any 
peer-reviewed publication will appropriately reflect contributions to the production and review 
of the document. All publications and presentations must be prepared in accordance with this 
section and the Clinical Study Site Agreement. In the event of any discrepancy between the 
protocol and the Clinical Study Site Agreement, the Clinical Study Site Agreement will prevail. 
Data from all sites participating in the study will be pooled and analyzed by PTC or PTC’s 
designee. The first publication of the study results shall be made in conjunction with the results 
from other study sites as a multicenter publication. If a multicenter publication is not 
forthcoming within 24 months of completion of the study at all sites, the investigator may 
publish or present the results generated at his or her site. 
The investigator will provide PTC with a copy of any proposed publication or presentation for 
review and comment at least 60 days prior to such presentation or submission for publication. 
PTC shall inform the investigator in writing of any changes or deletions in such presentation or 
publication required to protect PTC’s confidential and proprietary technical information and to 
address inaccurate data or inappropriate interpretations in the context of any pooled multicenter 
results. At the expiration of such 60-day period, the investigator may proceed with the 
presentation or submission for publication unless PTC has notified the institution or the 
investigator in writing that such proposed publication or presentation discloses PTC’s 
confidential and proprietary technical information. Furthermore, upon the request of PTC, the 
investigator will delay the publication or presentation for an additional 90 days to permit PTC to 
take necessary actions to protect its intellectual property interests. 

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15. 
PROTOCOL AMENDMENT HISTORY 
Version 1.0: 21 September 2021 
Version 2.0: 09 December 2021 
Version 3.0: 03 February 2022 
Version 4.0: 03 June 2022 
Version 5.0: 15 December 2022 
Version 6.0: 05 October 2023 
15.1. 
Version 6.0: 05 October 2023 
The overall reason for Version 6.0 of the protocol was to add reference to the Phase 2 long-term 
extension study (PTC518-CNS-004-HD). 
Section # 
Version 6.0/Description of Change 
Reason/Rationale 
Protocol 
The version number and date were updated throughout. 
Editorial and administrative revisions (eg, typographical 
errors, punctuation, tenses, abbreviations) were 
incorporated to provide clarity.  
The synopsis and Schedule of Assessments were updated 
to be consistent with changes in the protocol. 
Update 
Section 1.1 
Table 4 
Section 8.2.2 
Section 8.2.4  
The Safety Follow-Up Period was revised to be 6 months 
throughout the protocol for consistency with the Schedule 
of Assessments 
Update 
Section 1.2 
Added that subjects will have the option to enroll into the 
Phase 2 long-term extension study upon completion of Visit 
8 of this study. 
Update 
Section 3.7 
Added a section to outline unscheduled visits and added 
that subjects may continue within this study attending 
unscheduled visits approximately every 3 months prior to 
the end of study visit if they intend on enrolling in the Phase 
2 long-term extension study, but that study is not yet locally 
approved for conduct. 
Update 
Table 4  
Corrected terminology in the notes for clarity. 
Extended the visit window to be 7 days where applicable. 
Divided the UHDRS assessment into its individual parts for 
clarity. 
Update 
Section 4.2 
Extended the definition of exclusion criterion 6 to be 
specific of what entails 
. 
Added any known hypersensitivity to PTC518 or its 
excipients to exclusion criterion 16. 
Update 
Section 7.2.2 
The description of UHDRS was updated to more accurately 
match the assessment questionnaire. 
Update 
Section 8.2.10.1 
Clarified that if progression of underlying disease is greater 
than that normally expected and meets expected criteria, or 
if the investigator considers that there may be a causal 
relationship between the study drug or protocol 
design/procedures and the disease progression, and meets 
the seriousness criteria, then it must be reported to PTC 
Pharmacovigilance Department within 24 hours of 
awareness. 
Update 

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15.2. 
Version 5.0: 15 December 2022 
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of 
Directive 2001/20/EC of the European Parliament and the Council of the European Union. 
Protocol 
Section 
Version 5/Update 
Reason/Rationale 
Protocol 
The version number and date were updated 
throughout. 
Editorial and administrative revisions (eg, typographical 
error, punctuation, tenses, abbreviations) and minor 
updates to the text were incorporated to provide clarity. 
The synopsis and Schedule of Assessments were 
updated to be consistent with changes in the protocol.  
Update 
Section 1 
Details outlining the HD-ISS staging system of HD 
were added. 
Update 
Section 1 
Section 1.1 
Figure 2 
The protocol was updated to define the population to 
be enrolled in the study as Stage 2 or Mild Stage 3 HD 
based on the HD-ISS staging criteria. 
The enrollment in the 
study was expanded to 
enroll those who either 
have not yet 
experienced functional 
decline or who only have 
very limited features of 
functional decline as this 
population is determined 
to be the most likely to 
benefit from stabilization 
of disease from 
treatment with PTC518. 
Section 1.1 
Section 4.5 
Section 5.4 
Specified that the UHDRS TFC and IS scores will be 
utilized for screening subjects. 
Specified that PINHD score will be utilized for 
stratification of the Stage 2 group only, and that the 
Mild Stage 3 group will be stratified by TFC score. 
Update 
Section 1.1 
Section 7.2.4 
Table 4  
Corrected the assessment of early motor changes to 
be via Opal wearable devices. 
Update 
Section 1.2 
Figure 2  
Specified that those with Mild Stage 3 disease will 
participate in Parts D, E, and F of the study. 
Update 
Section 1.2 
Figure 1 
Added an additional Follow-Up Safety Visit on Month 
18. 
For a final evaluation of 
adverse events and 
pregnancy testing 6 
months after the last 
dose of study drug. 
Section 1.3.1 
Added a section detailing the summary of safety risks, 
aligning content with the Investigator’s Brochure. 
Update 
Section 2.2 
Section 2.7 
Added the change in cUHDRS as a secondary 
objective and endpoint, previously an exploratory 
objective and endpoint. 
Specified the secondary objective of mHTT protein in 
CSF and blood mHTT levels to be at Month 12. 
Update 

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Protocol 
Section 
Version 5/Update 
Reason/Rationale 
Section 2.3 
Section 2.8 
Added the change from Baseline in CSF and blood 
mHTT protein at Month 3 as exploratory objectives and 
endpoints. 
Changed the endpoints of change from Baseline in 
whole brain, putamen, and ventricular volume, UHDRS 
sub-scores, PBA-s, and TUG, 2-minute walk distance, 
and postural sway, and FuRST 2.0 questionnaire from 
over time to at Month 12. 
Specified the UHDRS sub-scores being evaluated as 
an exploratory endpoint. 
Update 
Section 3.1 
Section 4 
Section 9.2 
Updated the number of subjects being enrolled in the 
study to be up to 252 to correspond with the addition of 
Mild Stage 3 subjects in the study. 
To broaden learning in 
this Phase 2 study to 
include more of HD early 
disease, adding Mild 
Stage 3 (per HD-ISS 
staging). Enrollment 
numbers were also 
adjusted due to 
increased power for the 
primary and key 
secondary endpoints 
with larger overall 
subject numbers. 
Table 4 
The Baseline period was extended to span from 
Days -22 to -1. 
To reduce the burden on 
subjects of performing 
multiple long baseline 
assessments in a 
relatively short 
timeframe. 
Table 4 
Specified that the safety follow-up visits must be 
performed for all subjects following either the EOS or 
ET visits. 
Update 
Table 4 
Table 5 
Section 8.1.10.2 
Modified the pregnancy testing to be monthly from Day 
1 through the last Safety Follow-up Visit. Stated that for 
when no in-person visit is scheduled, a home 
pregnancy test will be taken by the subject and 
reported to the investigator. 
Update 
Table 4 
Section 8.1.7 
Transpupillary photographs were removed from the 
study. 
To reduce the burden on 
subjects, as nonclinical 
toxicology data (as 
shared in the IB) 
indicate that it is safe to 
remove this assessment 
from the clinical study 
Table 4  
PBA-s assessment was removed from Visits 5, 6, and 
7 as it will only be conducted in place of Part III of the 
UHDRS on applicable visits (ie, Visits 2 and 8). 
Update 
Table 4 
Section 4.2 
Section 8.1.10 
Updated language surrounding the C-SSRS versioning 
that will be utilized in the study for consistency among 
study documentation. 
Update 

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Protocol 
Section 
Version 5/Update 
Reason/Rationale 
Section 4.1 
Modified the CAG repeat length to qualify for 
enrollment to be from 40 to 50, inclusive. 
Inclusion criteria has been added to delineate Stage 2 
and Mild Stage 3 HD. 
Update 
Section 4.1 
Section 8.2.11.3 
Bilateral tubal ligation was removed as an acceptable 
method of permanent sterilization. 
Update 
Section 4.2 
Specified that participation in observational studies is 
not exclusionary for the study. 
Update 
Section 4.2 
A diagnosis of Juvenile-Onset HD will be excluded 
from the study. 
To keep the subject 
population as 
homogenous as 
possible, as Juvenile-
Onset HD is considered 
a different disease. 
Section 5.3 
Specified that treatment compliance is defined as 
taking ≥80% of the medication over the course of the 
study. 
Update 
Section 6.1 
Modified the description of the study drug for clarity. 
Removed information on the composition of the drug 
product as this is provided in other study documents. 
Update 
Section 6.3 
Modified to refer to the pharmacy manual or clinical 
label for storage conditions of the active and placebo. 
Update 
Section 6.4 
Section 6.4.1 
Removed the requirement to take the study drug prior 
to the first meal of the day. 
Update 
Section 9.3.1 
Section 9.3.3.1 
Section 9.3.3.2 
Section 9.3.3.3 
Modified the statistical methods in accordance with the 
added group of subjects being evaluated and the 
change in study endpoints. 
Update 
Section 9.4 
Added in details regarding planned interim analyses. 
Update 
Section 9.6 
Expanded on missing data methodology. 
Update 
Section 12.3 
Section 13.3 
Modified the use of remaining mandatory samples for 
optional exploratory research, and consent required for 
such activities. 
Update 
15.3. 
Version 4.0: 03 June 2022 
Protocol 
Section 
Version 4/Update 
Reason/ 
Rationale 
Protocol 
The protocol was updated throughout to extend the study to be 
12 months of treatment duration, followed by 2 Safety Follow-Up 
Visits 1 and 4 months after the last dose of study drug. The Schedule 
of Assessments was updated accordingly to account for the additional 
visits and the planned assessments for each visit. The Schedule of 
Assessments was also revised for clarity. 
The protocol was updated throughout to refer to Months rather than 
Days 
The version number and date were updated throughout. 
Editorial and administrative revisions (eg, typographical error, 
punctuation, tenses, abbreviations) and minor updates to the text 
were incorporated to provide clarity. The synopsis and Schedule of 
Assessments were updated to be consistent with changes in the 
protocol.  
Update 

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Protocol 
Section 
Version 4/Update 
Reason/ 
Rationale 
Section 2.1 
Section 2.2 
Section 2.3 
Section 2.5 
Section 2.7 
Section 2.8 
Section 2.9  
The primary pharmacodynamic objective was more clearly defined. 
Assessing the effects of PTC518 on change in caudate volume via 
vMRI was moved from an exploratory objective to the key secondary 
objective and endpoint of the study. 
 
 
. 
A secondary endpoint for blood tHTT protein at Month 12 was added 
to coincide with the primary endpoint of blood tHTT protein at 
Month 3. 
An exploratory endpoint for the cUHDRS score at Month 12 was 
added. 
The effect of PTC518 on blood HTT mRNA was changed to be an 
exploratory objective and endpoint. 
Plasma and CSF NfL were added as exploratory endpoints, in 
addition to the safety endpoints. 
The endpoints’ timepoints were updated throughout to be consistent 
with the change in treatment duration to 12 months. 
Update 
Section 3.3 
The dose justification section was revised to include updated 
nonclinical toxicology information from recently completed studies. 
Update 
Section 4.1 
Removed reference to legally authorized representative throughout 
the protocol. 
Specified that CAG repeat length may be determined analytically 
through amplification. 
Added that female partners of enrolled males who are of childbearing 
potential should consider use of highly effective methods of 
contraception. 
Added definitions for acceptable use of abstinence as a form of 
contraception. 
Added bilateral tubal ligation as a form of permanent sterilization. 
Update 
Section 4.2 
Specified that the inability to fast would preclude inclusion from the 
study. 
Added that antipsychotic use is not permitted unless receiving stable 
doses at least 6 weeks prior to Screening and with a dose regimen 
that is not anticipated to change during the study. 
Added that benzodiazepine use for sedation for study-related 
procedures during the course of the study is permitted. 
Update 
Section 7.1 
Specified the total volumes of blood and CSF to be collected during 
the study and added reference that individual volumes to be collected 
are documented in a separate instruction laboratory manual. 
Update 
Section 8.1.5 
 
Update 
Section 8.1.9  
Table 5 
Uric acid added to the list of clinical laboratory assessments, and 
clarification provided about local laboratory assessment of CSF WBC, 
RBC, protein, and glucose. 
Update 
Section 8.2 
Entirety of the safety reporting section was revised to align with 
updated safety reporting language in accordance with 
PTC Pharmacovigilance. 
Update 
Section 9 
Updated the definitions of the ITT and Safety Populations for clarity. 
A Per Protocol Population was added. 
Updated the statistical methodology throughout to be in line with the 
extension of study duration and revisions to study endpoints. 
Revised so that an interim analysis may be performed at any time. 
Methods of missing data handling was revised. 
Update 

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Protocol 
Section 
Version 4/Update 
Reason/ 
Rationale 
Section 13.4 
Added a section on Data Protection to outline the methods used. 
Update 
15.4. 
Version 3.0: 03 February 2022 
Protocol 
Section 
Version 3/Update 
Reason/ 
Rationale 
Protocol 
The protocol was updated throughout to reflect a 3-part design with a 
DSMB recommendation occurring prior to the initiation of Part C. The 
nature of the objectives and associated endpoints was clarified, and 
the descriptions of assessments were simplified. The version number 
and date were updated throughout. 
Editorial and administrative revisions (eg, typographical error, 
punctuation, tenses, abbreviations) and minor updates to the text were 
incorporated to provide clarity. The synopsis and Schedule of 
Assessments were updated to be consistent with changes in the 
protocol.  
Update/ 
Clarification 
Section 1.1 
Study rationale updated to reflect 3-part design 
Update 
Section 1.2 
Study description updated to a 3-part design, behavioral scale on 
UHDRS replaced with the PBA-s, and CGI-C is eliminated. 
Update 
Section 2.3 
Behavioral scale on UHDRS replaced with the PBA-s in list of 
exploratory objectives, CGI-C eliminated. 
Update 
Section 2.8 
Description of endpoints edited to reflect that the PBA-s will replace 
the behavioral scale on the UHDRS and the elimination of the CGI-C. 
Update 
Section 3.1 
Number of subjects updated to reflect 54 per Study Part 
Update 
Section 3.2 
Description of randomization updated to reflect 3-part design 
Update 
Section 4 
Description of sample size updated to reflect 3-part design 
 
Section 4.2 
Glomerular filtration rate unit corrected and reference to LOCSIII 
grading scale deleted 
Clarification 
Table 4 
Schedule of Assessments updated for clarification and to reflect 
changes to assessments indicated throughout the protocol.  
Update/ 
Clarification 
Section 5.4 
Description of randomization updated to reflect 3-part design 
Update 
Section 7.2 
Description of clinical scales revised to replace UHDRS Behavioral 
Examination with PBA-s, eliminate CGI-C, and clarify use of 
assessments.  
Update 
Section 7.2.1 
Description of UHDRS revised to reflect that the PBA-s will replace the 
behavioral scale on the UHDRS 
Update 
Section 7.2.2 
Description of the PBA-s added to reflect that the PBA-s will replace 
the behavioral scale on the UHDRS, Section devoted to CGI-C was 
deleted 
Update 
Section 7.2.3 
Language added to reflect that each gait and motor assessment test 
will be conducted twice. 
Update 
Section 8.1.4 
Text updated to delete reference to abbreviated physical examination, 
which is not be used in this study 
Update 
Section 8.1.7 
Text updated to delete reference to LOCSIII grading scale, which will 
not be used in this study 
Update 
Section 8.1.9 
Text updated to reflect that NfL will be assessed in plasma, rather 
than serum. 
Update 
Section 9.2 
Description of sample size updated to reflect 3-part design 
Update 
Section 9.3.3.3  Description of analysis edited to reflect that the PBA-s will replace the 
behavioral scale on the UHDRS and the elimination of the CGI-C. 
Update 

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15.5. 
Version 2.0: 09 December 2021 
Overall reason for Version 2.0: The overall reason for Version 2.0 of the protocol was to 
incorporate Health Authority feedback. 
Protocol 
Section 
Version 2/Update 
Reason/ 
Rationale 
Protocol 
The protocol was updated throughout to add a third PTC518 dose and to 
make the study a 2-part design. The version number and date were 
updated throughout. 
Editorial and administrative revisions (eg, typographical error, punctuation, 
tenses, abbreviations) and minor updates to the text were incorporated to 
provide clarity. The synopsis and Schedule of Assessments were updated 
to be consistent with changes in the protocol.  
Update 
Section 1.2  
The study design section was moved here and updated to reflect the 2-
part, 3 dose (plus placebo) design and to introduce the DSMB role in 
moving to Part B of the study. 
Update 
Section 1.3  
Rationale for the doses selected was added together with DSMB details.  
Update 
Section 2 
Section 7  
NfL plasma and CSF levels, 
, and FuRST 2.0 
assessments were added as objectives and the HD Quality of Life 
questionnaire was removed. The endpoints and clinical assessments were 
updated accordingly. 
Update 
Section 3  
The Study Design section was removed and included instead in Section 1 
Clarification 
Section 3.1, 
Section 4, 
Section 9.2  
The number of subjects was increased to reflect the added dose level. 
Update 
Section 3.2 
Section 5.4  
Randomization and treatment details were updated to reflect the new 
study design. Stratification was also added. 
Update 
Section 3.3  
Model predictions were added as rationale of the dose selection.  
Clarification 
Section 3.6  
Clarification of possible home care assessments was added.  
Clarification 
Section 4.2  
Exclusion criterion #15 was updated to clarify use of illicit drugs or alcohol 
and #19 was updated to specify that subjects should not become pregnant 
within 6 months of end of treatment. 
Clarification 
Section 8  
NfL levels were added to the safety parameters and vital signs, ECGs and 
laboratory test abnormalities were specified, rather than changes from 
baseline. Neurological examinations were removed. 
Update and 
clarification 

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16. 
REFERENCES 
Caron, N, Wright, G and Hayden, M (2020a). Huntington Disease. In GeneReviews (Internet). 
N. Adam, H. Ardinger, R. Pagon and e. al.; Seattle, WA, University of Washington. 
Caron, NS, Southwell, AL, Brouwers, CC, Cengio, LD, Xie, Y, Black, HF, et al. Potent and 
Sustained Huntingtin Lowering via AAV5 Encoding miRNA Preserves Striatal Volume and 
Cognitive Function in a Humanized Mouse Model of Huntington Disease. Nucleic Acids Res 
2020b;48(1):36-54. 
Cattaneo, E, Rigamonti, D, Goffredo, D, Zuccato, C, Squitieri, F and Sipione, S. Loss of Normal 
Huntingtin Function: New Developments in Huntington's Disease Research. Trends Neurosci 
2001;24(3):182-188. 
Ehrhardt, A, Langbehn, D, Sathe, S, Macdonald, D, Sampaio, C (2021). Summary of 
Performance Analysis of CSF Sample Analysis Assays, HDClarity. 
Evers, MM, Miniarikova, J, Juhas, S, Vallès, A, Bohuslavova, B, Juhasova, J, et al. AAV5-
miHTT Gene Therapy Demonstrates Broad Distribution and Strong Human Mutant Huntingtin 
Lowering in a Huntington's Disease Minipig Model. Mol Ther 2018;26(9):2163-2177. 
FDA (2019). Guidance for Industry: Enrichment Strategies for Clinical Trials to Support 
Determination of Effectiveness of Human Drugs and Biological Products. 
FDA (2020). Code of Federal Regulations Title 21 Part 312: Investigational New Drug 
Application, Subpart D. Responsibilities of Sponsors and Investigators. 
Garriga-Canut, M, Agustin-Pavon, C, Herrmann, F, Sanchez, A, Dierssen, M, Fillat, C, et al. 
Synthetic Zinc Finger Repressors Reduce Mutant Huntingtin Expression in the Brain of R6/2 
Mice. Proc Natl Acad Sci U S A 2012;109(45):E3136-3145. 
Kordasiewicz, HB, Stanek, LM, Wancewicz, EV, Mazur, C, McAlonis, MM, Pytel, KA, et al. 
Sustained Therapeutic Reversal of Huntington's Disease by Transient Repression of Huntingtin 
Synthesis. Neuron 2012;74(6):1031-1044. 
Li, S and Li, XJ. Multiple Pathways Contribute to the Pathogenesis of Huntington Disease. Mol 
Neurodegener 2006;1:19. 
Long, J, Langbehn, D, Tabrizi, SJ, Landwehrmeyer, GB, Paulsen, JS and Warner, J. Validation 
of a Prognostic Index for Hungtington's Disease. Mov Disord 2017;2(32):256-263. 
Lu, B and Palacino, J. A Novel Human Embryonic Stem Cell-Derived Huntington’s Disease 
Neuronal Model Exhibits Mutant Huntingtin (mHTT) Aggregates and Soluble mHTT-Dependent 
Neurodegeneration. FASEB J 2013;27:1820-1829. 
Miniarikova, J, Evers, MM and Konstantinova, P. Translation of MicroRNA-Based Huntingtin-
Lowering Therapies From Preclinical Studies to the Clinic. Mol Ther 2018;26(4):947-962. 
Ouyang, J, Carroll, KJ, Koch, G and Li, J. Coping With Missing Data in Phase III Pivotal 
Registration Trials: Tolvaptan in Subjects With Kidney Disease, a Case Study. Pharm Stat 
2017;16(4):250-266. 
Prados, F, Cardoso, MJ, Leung, K, Cash, DM, Modat, M, Fox, NC, et al. Measuring Brain 
Atrophy With a Generalized Formulation of the Boundary Shift Integral. Neurobiol Aging 
2015;36:81-90. 

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Rubin, DB (1987). Multiple Imputation for Nonresponse in Surveys; John Wily & Sons, Inc. 
Stanek, LM, Sardi, SP, Mastis, B, Richards, AR, Treleaven, CM, Taksir, T, et al. Silencing 
Mutant Huntingtin by Adeno-Associated Virus-Mediated RNA Interference Ameliorates Disease 
Manifestations in the YAC128 Mouse Model of Huntington's Disease. Hum Gene Ther 
2014;25(5):461-474. 
Tabrizi, SJ, Ghosh, R and Leavitt, BR. Huntingtin Lowering Strategies for Disease Modification 
in Huntington's Disease. Neuron 2019;101(5):801-819. 
Tabrizi, SJ, Schobel, S, Gantman, E, Mansbach, A, Borowsky, B and Konstantinova, P. A 
biological classification of Huntington's disease: the integrated staging system. Lancet Neurol 
2022;21:632-644. 
Wang, N, Gray, M, Lu, XH, Cantle, JP, Holley, SM, Greiner, E, et al. Neuronal Targets for 
Reducing Mutant Huntingtin Expression to Ameliorate Disease in a Mouse Model of 
Huntington's Disease. Nat Med 2014;20(5):536-541. 
Yamamoto, A, Lucas, JJ and Hen, R. Reversal of Neuropathology and Motor Dysfunction in a 
Conditional Model of Huntington's Disease. Cell 2000;101(1):57-66. 
Zuccato, C, Ciammola, A, Rigamonti, D, Leavitt, BR, Goffredo, D, Conti, L, et al. Loss of 
Huntingtin-Mediated BDNF Gene Transcription in Huntington's Disease. Science 
2001;293(5529):493-498. 
 

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17.
APPENDICES
APPENDIX 1. 
RESTRICTED AND PROHIBITED MEDICATIONS 
Drug Name 
CYP3A4 Inhibitor
CYP3A4 Inducer 
Strength
Aprepitant 
X 
Moderate 
Boceprevir 
X 
Strong 
Bosentan 
X 
Moderate 
Carbamazepine 
X 
Strong 
Cimetidine 
X 
Moderate 
Ciprofloxacin 
X 
Moderate 
Clarithromycin 
X 
Strong 
Clotrimazole 
X 
Moderate 
Cobicstat 
X 
Strong 
Conivaptan 
X 
Strong 
Crizotinib 
X 
Moderate 
Cyclosporine 
X 
Moderate 
Danoprevir/Ritonavir 
X 
Strong 
Diltiazem 
X 
Strong 
Dronedarone 
X 
Moderate 
Efavirenz 
X 
Moderate 
Elvitegravir/Ritonavir 
X 
Strong 
Enzalutamide 
X 
Strong 
Erythromycin 
X 
Moderate 
Etravirine 
X 
Moderate 
Fluconazole 
X 
Moderate 
Fluvoxamine 
X 
Moderate 
Grapefruit Juice 
X 
Strong 
Idelalisib 
X 
Strong 
Imatinib 
X 
Moderate 
Indinavir/Ritonavir 
X 
Strong 
Itraconazole Ketoconazole 
X 
Strong 
Lopinavir/Ritonavir 
X 
Strong 
Mitotane 
X 
Strong 
Modafinil 
X 
Moderate 
Nefazodone 
X 
Strong 
Nelfinavir 
X 
Strong 
Paritaprevir/Ritonavir/Ombitasvir 
X 
Strong 
Phenytoin 
X 
Strong 
Posaconazole 
X 
Strong 
Rifampin 
X 
Strong 
Ritonavir 
X 
Strong 
Saquinavir/Ritonavir 
X 
Strong 
St. John’s Wort 
X 
Strong 
Telaprevir 
X 
Strong 
Tipranavir/Ritonavir 
X 
Strong 
Tofisopam 
X 
Moderate 
Troleandomycin 
X 
Strong 
Verapamil 
X 
Moderate 
Voriconazole 
X 
Strong 
Abbreviations: CYP, cytochrome P450 

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APPENDIX 2. 
WORLD HEALTH ORGANIZATION RISK DRINKING LEVELS 
Risk Level  
Definition of Each Level (in grams and US Standard Drinks) 
Very High  
>100 g (>7.1 drinks) for men; >60 g (>4.3 drinks) for women  
High  
60-100 g (4.3-7.1 drinks) for men; 40-60 g (2.9-4.3 drinks) for women  
Moderate  
40-60 g (2.9-4.3 drinks) for men; 20-40 g (1.4-2.9 drinks) for women  
Low  
1-40 g (<2.9 drinks) for men; 1-20 g (<1.4 drinks) for women  
Abbreviations: US, United States 
Source: A Reduction in the World Health Organization Risk Levels of Alcohol Consumption as an Efficacy Outcome 
in Alcohol Use Disorder Clinical Trials 

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