A Phase 3, Multicenter, Open-label Safety Study to Evaluate the Long-term Safety and Tolerability of SAGE-718 in Participants With Huntington's Disease
Phase: PHASE3
Conditions: Huntington's Disease
Sponsor: Supernus Pharmaceuticals, Inc.

 
Official Title: A Phase 3, Multicenter, Open-Label Safety Study to Evaluate 
the Long-Term Safety and Tolerability of SAGE-718 in 
Participants with Huntington’s Disease 
NCT Number: NCT05655520 
Document Date: Protocol Version 3: 05 February 2024 
 
 

Clinical Protocol 
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718-CIH-301, Version 3 
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INVESTIGATOR’S AGREEMENT 
I have received and read the investigator’s brochure for SAGE-718. I have read the 718-CIH-301 
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 (DD Month YYYY) 

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Study Description: 
This is a long-term, open-label study to evaluate the safety and tolerability of SAGE-718 in rollover 
participants from Phase 2 placebo-controlled studies and de novo participants with premanifest or early 
manifest HD. 
Participants will be adults with genetically confirmed expansion of the cytosine-adenine-guanine (CAG) 
trinucleotide repeat within the huntingtin gene, who meet the eligibility criteria. An adult study partner is 

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Eligibility Criteria: 
Inclusion Criteria 
Participants must meet all the following criteria to qualify for participation in this study: 
For all participants: 
1. Completed 718-CIH-201 or 718-CIH-202 studies or meet eligibility criteria for 
the de novo cohort. 
2. Be capable of providing informed consent in the opinion of the investigator (all 
cohorts) or be willing to have a legally authorized representative provide informed 
consent on their behalf (for 718-CIH-201 or 718-CIH-202 completers only). 
3. Have signed (or a legally authorized representative has signed, if applicable) an 
informed consent form prior to any study-specific procedures being performed.  
4. Agree to adhere to the study requirements. 
5. Be capable of complying with study procedures, in the opinion of the investigator. 
6. Be willing to invite a study partner, if available, who is reliable, competent, and at 
least 18 years of age to participate in the study. 
7. Be able to travel to the study center, and, judged by the investigator, is likely to be 
able to continue to travel to the study center to complete study visits for the 
duration of the study. 
8. [Revised in protocol version 3.0] 
8.A. Agree, if female, to use at least one method of highly effective contraception 
(refer to Section 9.2.4 for further details on acceptable forms of contraception) 
during participation in the study and for 30 days following the last dose of IP, 
unless she is postmenopausal (defined as no menses for 12 months without an 
alternative medical cause and confirmed by follicle-stimulating hormone 
>40 mIU/mL), permanently sterile, or does not engage in sexual relations which 
carry a risk of pregnancy.  
9. [Revised in protocol version 3.0] 
9.A. Agree, if male, to use an acceptable method of effective contraception for the 
duration of study and for 21 days after receiving the last dose of IP, unless the 
participant does not engage in sexual relations which carry a risk of pregnancy. 
Acceptable methods of effective contraception are listed in Section 9.2.4. 
10. [Revised in protocol version 3.0] 
10.A. Agree, if male, to abstain from sperm donation during the treatment period and 
for 21 days after receiving the last dose of IP. 
11. Agree to refrain from drugs of abuse for the duration of the study and from 
alcohol during the 48 hours preceding each study visit. 
Additional inclusion criteria for the de novo cohort (Cohort 3) 
12. Be at least 25 years old, but not older than 65 years of age at Screening. 
13. Meet all of the following criteria for HD: 
a. Genetically confirmed disease with CAG expansion ≥40 
b. No features of juvenile HD  
c. CAG-Age-Product (CAP) score ≥90, as calculated using the CAP formula: 
AGE × (CAG – 30) / 6.49. 
14. [Revised in protocol version 3.0] 
14.A. At Screening, scores of EITHER 

Clinical Protocol 
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a. UHDRS-TFC=13 and MoCA ≤25,  OR 
b. UHDRS-TFC ≤12 and MoCA >25 
15. Completion of HD-CAB Trail Making-B Test in <240 seconds at Screening 
(Days -28 to -1). 
Exclusion criteria 
Participants who meet any of the following criteria are disqualified from participation in this study: 
For all participants 
1. Have a diagnosis of an ongoing neurodegenerative condition other than HD, including but not 
limited to, Alzheimer’s Disease, vascular dementia, dementia with Lewy bodies, or Parkinson’s 
Disease. 
2. Have been diagnosed with and/or treated for any type of cancer (except successfully treated, 
locally excised basal cell carcinoma and melanoma in situ) within the past year prior to screening. 
3. Had gastric bypass surgery, have a gastric sleeve or lap band, or have had any related procedures 
that interfere with gastrointestinal transit. 
4. Plan to undergo elective surgery during participation in the study. 
5. Receive any of the following prohibited medications within 30 days of screening and during 
participation in the study: 
a. Medications with potent effects at the N-methyl-D-aspartate (NMDA) receptor, including 
amantadine, memantine, ketamine, cycloserine, or related compounds. 
b. Medications that inhibit cholesterol absorption (eg, ezetimibe). 
c. Bile acid sequestrants (eg, colesevelam, colestipol, cholestyramine). 
d. Other medications given at doses or in combinations that are likely to have a deleterious 
effect on cognitive performance, as determined by the investigator. 
e. Tetrahydrocannabinol-containing substances (any route of administration), regardless of 
whether they are prescribed. 
6. Take any psychotropic medications, including antidepressants and anxiolytics, unless the dose 
and frequency have been stable for at least 30 days prior to the first IP administration and are 
expected to remain stable for the duration of the study. 
7. Have an ongoing medical or psychiatric condition that, in the opinion of the investigator, may 
compromise the participant’s safety or compliance with study requirements. 
8. Have supine vital signs outside of the following ranges at Screening or Baseline (vital sign 
measurements may be repeated once per visit for initial values outside these ranges): 
a. Heart rate <50 or >100 bpm, 
b. Systolic blood pressure <100 or >160 mmHg, 
c. Diastolic blood pressure <60 or >100 mmHg. 
9. Have an alcohol or drug use disorder within the past 2 years, as assessed by the investigator. A 
positive urine drug screen is exclusionary unless deemed by the investigator to reflect a 
prescribed medication. 
10. Have a history of significant hand injury that would preclude either writing or rapid bimanual 
computerized responding. 

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11. Have a history of seizures or epilepsy, except for a single episode of febrile seizures in childhood. 
12. Have a history of brain surgery, a significant head injury causing loss of consciousness greater 
than 30 minutes, or hospitalization due to a brain injury. 
13. Have a history, presence, and/or current evidence of intracranial abnormality (eg, stroke, 
hemorrhage, space-occupying lesion). 
14. Have a positive pregnancy test, be pregnant, be lactating, or intend to breast feed during the 
study. 
15. Be investigative site personnel, sponsor personnel, or an immediate member of their family 
(spouse, parent, child, or sibling whether biological or legally adopted). 
16. Is known to be allergic to any of SAGE-718 excipients, including soy lecithin. 
Additional exclusion criteria for 718-CIH-201/202 completers who enroll after a gap of >7 days since 
completion of the parent study (Cohort 2) and for the de novo cohort (Cohort 3): 
17. Have a history, presence, and/or current evidence of serologic positive results for human 
immunodeficiency virus (HIV)-1/HIV-2 or hepatitis B or hepatitis C. 
Additional exclusion criteria for the de novo cohort (Cohort 3):  
18. Have previous exposure to gene therapy, or have participated in any other HD investigational 
drug, biologic, or device trial within 180 days or a non-HD drug, biologic or device trial within 
30 days or 5 half-lives (whichever is longer). Participants with confirmation of enrollment in the 
placebo arm of these investigational trials would not be excluded. Additionally, participants who 
have received treatment with antisense oligonucleotides or an mRNA splicing modifier will be 
excluded. 
19. Have current or recent suicidality, defined as follows: 
a. Suicidal ideation within the past month, as evidenced by a “Yes” on question 4 (active 
suicidal ideation with some intent to act, without specific plan) or question 5 (active suicidal 
ideation with specific plan and intent) on the ‘suicidal ideation’ items on the C-SSRS. 
b. Suicidal behavior within the past year, as evidenced by a "Yes" on any of the Suicidal 
Behavior items on the C-SSRS. 
c. Presenting a serious risk of suicide in the opinion of the investigator. 
Additional exclusion criteria for 718-CIH-201/202 completers (Cohorts 1 and 2): 
20. Have current or recent suicidality, defined as follows: 
a. Suicidal ideation since last visit, as evidenced by a “Yes” on question 4 (active suicidal 
ideation with some intent to act, without specific plan) or question 5 (active suicidal ideation 
with specific plan and intent) on the ‘suicidal ideation’ items on the C-SSRS. 
b. Suicidal behavior since last visit, as evidenced by a "Yes" on any of the Suicidal Behavior 
items on the C-SSRS. 
c. Presenting a serious risk of suicide in the opinion of the investigator. 
21. Have one or more ongoing serious adverse events from the parent study that were assessed as 
related to IP. 
22. Have ongoing, unresolved AE(s), which in the opinion of the investigator or sponsor, are likely to 
interfere with study conduct or compliance. 

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Table 3: 
Schedule of Assessments:  Day 1 to Month 12 [718-CIH-201/202 Direct (≤7 days) Rollover (Cohort 1) 
Participants] 
Assessments  
Carry-over Results of 
the Last Assessments 
from Parent Studies 
when Applicablea,f 
Treatment Period 
Day 1 
Day 30 
(±7 days) 
Day 60 
(±7 days) 
Day 90 
(±7 days) 
Day 180 
(±14 days) 
Day 270 
(±14 days) 
Day 365 
(±14 
days)b  
Informed consentc 
 
X 
 
 
 
 
 
 
Inclusion/exclusion criteria 
 
X 
 
 
 
 
 
 
Family history and 
demographics 
X 
 
 
 
 
 
 
 
Medical historyd 
X 
X 
 
 
 
 
 
 
Participant traininge 
 
X 
 
 
 
 
 
 
Body weight 
 
Xf 
 
 
 
X 
 
X 
Body height 
X 
 
 
 
 
 
 
 
Vital signs (including 
orthostatics)g  
 
Xf 
X 
X 
X 
X 
X 
X 
Physical examinationh 
X 
 
X 
X 
X 
X 
X 
X 
CAG test  
X 
 
 
 
 
 
 
 
FSH test 
X 
 
 
 
 
 
 
 
Serology testi 
X 
 
 
 
 
 
 
 
12-lead ECGj 
X 
 
X 
 
X 
X 
 
X 
Safety laboratory assessmentsk 
X 
 
X 
 
X 
X 
X 
X 
Urine drug test 
 
Xf 
X 
X 
X 
X 
 
X 
Alcohol breath test 
 
Xf 
X 
X 
X 
X 
 
X 
Cigarette/tobacco use 
assessment 
 
Xf 
X 
X 
X 
X 
 
X 
Pregnancy testl 
X 
 
X 
 
X 
X 
X 
X 
C-SSRS (Since Last Visit) 
X 
 
X 
X 
X 
X 
X 
X 

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b 
Participants who have NOT completed their Day 395 visit under Protocol Version 2 but have completed their Day 365 visit and wish to continue 
participation under Protocol Version 3 or higher will NOT return to the site for a Re-Qualification Visit.  They will return to the site for a Study Continuation 
Visit (Appendix 2, Section 20.2) and then continue on to their Month 15 visit (see Table 5).  The participant’s visit schedule should remain relative to the 
date of their Day 1 visit. 
c 
718-CIH-301 v2 Completers will resume IP at their Next Scheduled Study Treatment Visit (see Table 5). The Next Scheduled Study Treatment Visit may be 
any visit within the Treatment Period and will depend on the participant’s visit schedule, which will remain relative to the date of their Day 1 visit.  
d 
Both participants and study partners (if applicable) will be re-consented at the Re-Qualification Visit. A legally authorized representative may consent on 
behalf of participants who are not capable of providing informed consent in the opinion of the investigator. 
e 
Guidance on eligibility for 718-CIH-301 v2 Completers is provided in Section 7.1.3.1. 
f 
Any new or worsening conditions or events with an onset after the end of participation under 718-CIH-301 Protocol Version 2 (Day 395) and before 
informed consent for 718-CIH-301 Protocol Version 3 or higher will be recorded as Interim Medical History in the eCRF.  
g 
Participants and study partners (if applicable) will be re-trained, if need be based on participant’s comfort level, by study staff on the use of software 
applications, devices, and diaries necessary for the conduct of the study.  
h 
Vital signs include body temperature, respiratory rate, heart rate, and blood pressure. Blood pressure and heart rate will be measured after the participant has 
been in the supine position for at least 5 minutes and then repeated approximately 1 and 3 minutes after standing at all scheduled time points. Vital signs can 
be repeated once if out of range. At the Post Re-Qualification Safety Check-in, vital signs will be measured prior to dosing. 
i 
A full physical and neurological examination is to be conducted during the Re-Qualification Visit. At the Post Re-Qualification Safety Check-in, physical 
examinations will include a brief assessment of general appearance, cardiovascular, respiratory, gastrointestinal, and neurological systems and followed by a 
targeted physical assessment as needed. A symptom-directed examination may be conducted at any time at the discretion of the investigator.  
j 
To include hepatitis B and C screening tests, HIV-1 and HIV-2 antibody. 
k 
A single ECG will be measured after the participant has been in the supine position for at least 5 minutes. 
l 
Safety laboratory assessments will include blood samples for hematology, biochemistry, coagulation, and urine samples for urinalysis. At the Post Re-
Qualification Safety Check-in, samples will be collected ≤2 hours prior to dosing.  
m 
Serum pregnancy tests will be conducted for all female participants at the Re-Qualification Visit.   
n 
At the Post Re-Qualification Safety Check-in, participants will self-administer IP in the clinic under the supervision of study staff. All scheduled safety 
assessments will be conducted prior to dosing.  
o 
AEs/SAEs will be collected from the time of informed consent for 718-CIH-301 Protocol Version 3 or higher through end of study participation.  
p 
All medications, supplements, procedures, and therapies taken after the completion of Day 395 under 718-CIH-301 Protocol Version 2 will be recorded 
through the end of the study.  
  
 
 

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Table 5: 
Schedule of Assessments: Month 15 to Month 48 – All Participants 
Assessments  
Treatment Perioda 
Safety 
Follow-Up  
 
M 15 
(±14 d) 
M 18 
(±14 d) 
M 21 
(±14 d) 
M 24 
(±14 d) 
M 27 
(remote) 
(±14 d) 
M 30 
(±14 d) 
M 33 
(remote) 
(±14 d) 
M 36 
(±14 d) 
M 39 
(remote) 
(±14 d) 
M 42 
(±14 d) 
M 45 
(remote) 
(±14 d) 
M 48 
or ETb 
(±14 d) 
  +30 days 
(±7 days) 
Body weight 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
Vital signs (including 
orthostatics)c 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
X 
Brief physical examinationd 
X 
X  
X 
X 
 
X 
 
X 
 
X 
 
X 
X 
12-lead ECGe 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Safety laboratory 
assessmentsf 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
Urine drug test 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
Alcohol breath test 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
Cigarette/tobacco use 
assessment 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
Pregnancy testg 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
C-SSRS (Since Last Visit) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 

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Table 6: 
 
 

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3. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF 
FIGURES  
TABLE OF CONTENTS 
1. 
TITLE PAGE ................................................................................................................1 
2. 
SYNOPSIS ...................................................................................................................4 
3. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES ...............27 
4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS.............................33 
5. 
INTRODUCTION ......................................................................................................36 
5.1. 
Overall Risk/Benefit Assessment ...............................................................................37 
5.2. 
Dose Justification ........................................................................................................38 
6. 
STUDY OBJECTIVES AND ENDPOINTS ..............................................................39 
7. 
INVESTIGATIONAL PLAN .....................................................................................41 
7.1. 
Overall Study Design ..................................................................................................41 
7.1.1. 
Study Schematic .........................................................................................................41 
7.1.2. 
Screening Period .........................................................................................................42 
7.1.3. 
Treatment Period ........................................................................................................42 
7.1.3.1. 
Additional visits related to the transition from Protocol Version 2 to Protocol 
Version 3 .....................................................................................................................43 
7.1.3.2. 
Remote Visits ..............................................................................................................43 
7.1.4. 
Follow-up Period ........................................................................................................44 
7.2. 
Number of Participants ...............................................................................................44 
7.3. 
Treatment Assignment ................................................................................................44 
7.4. 
Dose Adjustment Criteria ...........................................................................................44 
7.4.1. 
......................................................................................44 
7.4.1.1. 
 .......................................................................................44 
7.4.2. 
Stopping Criteria .........................................................................................................45 
7.4.3. 
Dose Modification in Potential Hy’s Law Cases ........................................................45 
7.4.4. 
Criteria for Study Termination ...................................................................................45 
7.4.5. 
End of Study ...............................................................................................................45 
8. 
SELECTION AND WITHDRAWAL OF PARTICIPANTS.....................................46 
8.1. 
Participant Inclusion Criteria ......................................................................................46 
8.2. 
Participant Exclusion Criteria .....................................................................................47 

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8.3. 
Screen Failures ............................................................................................................49 
8.4. 
Investigational Product Discontinuation and Early Termination from the 
Study ...........................................................................................................................49 
8.4.1. 
Loss to Follow-up .......................................................................................................50 
8.4.2. 
Replacement of Participants .......................................................................................50 
9. 
TREATMENT OF PARTICIPANTS .........................................................................51 
9.1. 
Description of Investigational Product .......................................................................51 
9.2. 
Prior Medications, Concomitant Medications, Restrictions, and 
Contraception Requirements ......................................................................................51 
9.2.1. 
Prior and Concomitant Medications, Supplements, and Procedures/Therapies .........51 
9.2.2. 
Prohibited Medications ...............................................................................................51 
9.2.3. 
Other Restrictions and Recommendations..................................................................52 
9.2.4. 
Acceptable Forms of Contraception ...........................................................................52 
9.3. 
Intervention After the End of the Study .....................................................................53 
9.4. 
Treatment Adherence ..................................................................................................53 
9.5. 
Randomization and Blinding ......................................................................................53 
10. 
INVESTIGATIONAL PRODUCT MATERIALS AND MANAGEMENT .............54 
10.1. 
Investigational Product ...............................................................................................54 
10.2. 
Investigational Product Packaging and Labeling .......................................................54 
10.3. 
Investigational Product Storage ..................................................................................54 
10.4. 
Investigational Product Preparation ............................................................................55 
10.5. 
Investigational Product Administration ......................................................................55 
10.5.1. 
Medication Adherence and Reminder System ...........................................................55 
10.5.1.1. 
Registration in the AiCure platform ...........................................................................55 
10.5.1.2. 
Ongoing Use and Monitoring of Medication Adherence ...........................................55 
10.6. 
Investigational Product Accountability, Handling, and Disposal ...............................56 
10.7. 
Product Complaints ....................................................................................................56 
11. 
SCREENING, EFFICACY, AND CLINICAL PHARMACOLOGY 
ASSESSMENTS.........................................................................................................57 
11.1. 
Screening Assessments ...............................................................................................57 
11.1.1. 
Montreal Cognitive Assessment (MoCA) ..................................................................57 
11.1.2. 
Cigarette and(or) Tobacco Use Assessment ...............................................................57 
11.2. 
 .................................................................................................57 

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11.2.1. 
 ..........58 
11.2.1.1. 
 .....................................................................................58 
11.2.1.2. 
 ...........................................................................58 
11.2.1.3. 
 ........................................................................................58 
11.2.1.4. 
 ......................................................................58 
11.2.1.5. 
 .....................................................................................................59 
11.2.1.6. 
 .........................................................................................59 
11.2.1.7. 
 .......................................................................59 
11.2.2. 
 ...............................................................59 
11.2.2.1. 
 ........................................................................................59 
11.2.2.2. 
 .........................................................................................60 
11.2.2.3. 
 .......................................................................60 
11.2.3. 
 .....................................60 
11.2.3.1. 
 ........................................................................................60 
11.2.3.2. 
 ............................................61 
11.2.3.3. 
 ........................................................................................................61 
11.2.3.4. 
 ....................................................61 
11.2.3.5. 
 ..............................................................61 
11.2.3.6. 
 ...................................................................................................62 
11.2.3.7. 
 .....................................................................62 
11.2.3.8. 
 ........................................................................................................62 
11.2.3.9. 
 ........................................................................................62 
11.2.4. 
 .........................................................62 
11.2.4.1. 
 ..........................................62 
11.2.5. 
 .............................................................63 
11.2.5.1. 
ge .............................................63 
11.2.5.2. 
 ........................................................................................................63 
11.2.6. 
 ..................................................................................63 
11.3. 
 ..........................................................................64 
11.3.1. 
 ....................................................................................64 
11.3.1.1. 
 ............................................................................................64 
11.3.1.2. 
 .........................................................................................................64 
11.3.2. 
 .................................................................................64 

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11.3.2.1. 
 .................................................................................64 
11.3.2.2. 
 .......................................................................65 
12. 
SAFETY ASSESSMENTS ........................................................................................66 
12.1. 
Safety Parameters .......................................................................................................66 
12.1.1. 
Demography and Medical History ..............................................................................66 
12.1.2. 
Weight and Height ......................................................................................................66 
12.1.3. 
Physical Examination .................................................................................................66 
12.1.4. 
Vital Signs ..................................................................................................................67 
12.1.5. 
Electrocardiogram .......................................................................................................67 
12.1.6. 
Laboratory Assessments .............................................................................................67 
12.1.6.1. 
Drugs of Abuse, Alcohol ............................................................................................69 
12.1.6.2. 
Pregnancy Testing ......................................................................................................69 
12.1.7. 
Columbia-Suicide Severity Rating Scale ....................................................................69 
12.1.8. 
COVID-19 Questions .................................................................................................69 
12.1.9. 
 .................................................................................69 
12.2. 
Adverse and Serious Adverse Events .........................................................................70 
12.2.1. 
Adverse Event Definition ...........................................................................................70 
12.2.2. 
Serious Adverse Event Definition ..............................................................................70 
12.2.3. 
Definition of Urgent Safety Measure and Unanticipated Problem .............................71 
12.2.4. 
Relationship to Investigational Product ......................................................................72 
12.2.5. 
Recording Adverse Events .........................................................................................72 
12.2.6. 
Reporting Serious Adverse Events .............................................................................73 
12.2.7. 
Assessment of Liver Biochemistry for Hy’s Law Screening, or Hy’s Law 
Laboratory Criteria .....................................................................................................73 
12.3. 
Pregnancy ...................................................................................................................74 
12.4. 
Special Considerations ................................................................................................75 
13. 
STATISTICS ..............................................................................................................76 
13.1. 
Data Analysis Sets ......................................................................................................76 
13.2. 
Handling of Missing Data ...........................................................................................76 
13.3. 
General Considerations ...............................................................................................76 
13.4. 
Demographics and Baseline Characteristics ...............................................................76 
13.5. 
 ........................................................................................................76 
13.6. 
Safety Analyses ..........................................................................................................77 

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13.6.1. 
Adverse Events ...........................................................................................................77 
13.6.2. 
Clinical Laboratory Evaluations .................................................................................77 
13.6.3. 
Physical Examinations ................................................................................................77 
13.6.4. 
Vital Signs ..................................................................................................................78 
13.6.5. 
12-Lead Electrocardiogram ........................................................................................78 
13.6.6. 
Prior and Concomitant Medications ...........................................................................78 
13.6.7. 
Columbia Suicide Severity Rating Scale ....................................................................78 
13.6.8. 
 ...................................................................78 
13.7. 
 ................................................................................79 
13.8. 
Sample Size and Power ..............................................................................................79 
14. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS.........................................80 
14.1. 
Study Monitoring ........................................................................................................80 
14.2. 
Audits and Inspections ................................................................................................80 
14.3. 
Institutional Review Board or Independent Ethics Committee ..................................81 
15. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................82 
16. 
ETHICS ......................................................................................................................83 
16.1. 
Ethics Review .............................................................................................................83 
16.2. 
Ethical Conduct of the Study ......................................................................................83 
16.3. 
Written Informed Consent ..........................................................................................83 
16.4. 
Data Protection ...........................................................................................................84 
17. 
DATA HANDLING AND RECORDKEEPING .......................................................85 
17.1. 
Inspection of Records .................................................................................................85 
17.2. 
Retention of Records ..................................................................................................85 
18. 
PUBLICATION POLICY ..........................................................................................86 
19. 
LIST OF REFERENCES ............................................................................................87 
20. 
APPENDIX.................................................................................................................89 
20.1. 
Appendix 1: Country-Specific Changes .....................................................................89 
20.2. 
Appendix 2: Study Continuation Visit for Participants Who Completed Day 
365 But Not Day 395 Under Protocol Version 2 ........................................................91 
 
 
 

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4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Table 7: 
Abbreviations and Specialist Terms  
Abbreviation 
Definition 
24(S)-HC 
24(S)-hydroxycholesterol 
718-CIH-301 v2 
Completers 
participants who have completed their Day 395 visit under Protocol 
Version 2 and wish to continue participation under Protocol Version 3 or 
higher 
ADME 
absorption, distribution, metabolism, and excretion 
AE 
adverse event 
AI 
Apathy Inventory 
 
 
CAG 
cytosine-adenine-guanine 
CAP 
CAG-Age-Product  
CFR 
Code of Federal Regulations 
 
  
 
 
Cmax  
maximum concentration 
COVID-19 
coronavirus disease 2019 
CS 
clinically significant 
C-SSRS 
Columbia–Suicide Severity Rating Scale  
 
  
DILI 
drug-induced liver injury 
ECG 
Electrocardiogram 
eCRF 
electronic case report form 
EEG 
electroencephalogram  
ET  
Early Termination  
FDA 
Food and Drug Administration 
FSH 
follicle-stimulating hormone 
 
 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 
GMP 
Good Manufacturing Practice 

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Abbreviation 
Definition 
 
 
SUSAR 
suspected unexpected serious adverse reaction 
TEAE 
treatment-emergent adverse event 
TFC 
Total Functional Capacity  
THC 
tetrahydrocannabinol  
TMS 
Total Motor Score 
UHDRS 
Unified Huntington’s Disease Rating Scale  
UP 
unanticipated problem 
US 
United States 
USM 
urgent safety measure  
 
  
 
  

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5. 
INTRODUCTION 
Huntington's disease (HD) is a rare, hereditary, neurodegenerative disease for which there is no 
approved pharmacologic therapy for the treatment of cognitive dysfunction. An estimated 18,600 
to 30,000 adults (7.3 to 11.8 per 100,000) have been diagnosed with HD in the United States 
(NINDS 2022; Rawlins 2016). Based on population estimates, there are approximately 41,000 
symptomatic Americans and more than 200,000 at-risk of inheriting HD (Huntington’s Disease 
Society of America 2022), highlighting the unmet medical need in this population. 
In the pre-motor stages of the disease, psychiatric and cognitive dysfunction predominate 
(Tabrizi 2012). Natural history studies have shown that cognitive decline begins to occur up to 
15 years before motor symptoms manifest and the formal diagnosis occurs. Later stages of the 
disease are characterized by prominent motor symptoms, including chorea and rigidity, though 
cognitive impairment remains an ongoing concern and a significant driver of functional disability 
(Cardoso 2017; Duff 2010). Intervention at an early stage of the disease may help patients 
maintain cognitive capacities critical to everyday functioning. 
Although the mechanisms underlying cognitive dysfunction in HD have not been fully 
elucidated, changes in glutamatergic neurotransmission have been implicated based on the 
results of nonclinical, postmortem, and clinical studies. Nonclinical studies have shown that 
moderate stimulation of N-methyl-D-aspartate (NMDA) receptors in an HD mouse model may 
impart neuroprotective effects (Okamoto 2009). Postmortem brain samples in a pre-symptomatic 
carrier of the HD allele reveal abnormalities of striatal NMDA receptors and projections to the 
globus pallidus and substantia nigra, suggesting core aspects of HD symptomatology may be 
consequential to reduction of NMDA signaling along these pathways (Albin 1990). Most 
important, reduction in plasma levels of 24(S)-hydroxycholesterol (24(S)-HC), an endogenous 
modulator of NMDA receptors, has been described in HD patients (Leoni 2013; Lewis 2019; 
Paul 2013). These data support proof of principle that lower 24(S)-HC levels in HD could reflect 
NMDA receptor dysfunction, as well as pathology relevant to in the etiology of associated 
cognitive deficits (Lewis 2019). 
SAGE-718 is a novel, first-in-class, oxysterol-based positive allosteric modulator of NMDA 
receptors. SAGE-718 acts at the 24(S)-HC site that modulates the response of the receptor to 
glutamate but does not directly activate it. Glutamate, the most prevalent excitatory 
neurotransmitter in the brain, primarily signals through ionotropic ligand-gated receptors and 
metabotropic G-protein-coupled receptors. NMDA receptors are a subtype of glutamate receptor 
with a fundamental and well-documented role in regulating synaptic strength, health, and 
plasticity (Vyklicky 2014; Yao and Zhou 2017). 
SAGE-718 is being developed as a novel early intervention to treat cognitive dysfunction 
associated with HD, for which there is no approved pharmacologic therapy. 
This is an open-label study to evaluate the long-term safety and tolerability of SAGE-718 in 
participants with premanifest or early manifest HD. Additional data on the effects of SAGE-718 
in participants with HD will be collected throughout, including assessments of cognitive, 
neuropsychiatric, and motor symptoms.  

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5.1. 
Overall Risk/Benefit Assessment 
The administration of SAGE-718 in premanifest and early manifest HD is expected to have 
moderate NMDA augmenting properties without impacting brain integrity, thereby improving 
cognition in HD patients and potentially alleviating one of the most significant and debilitating 
symptoms associated with the disease. This hypothesis is supported by the emerging clinical data 
revealing that the administration of SAGE-718, a novel and optimized analogue of 24(S)-HC, 
improves performance on tests of higher-order functioning in patients with pre-manifest or early 
manifest HD as well as in healthy participants with a ketamine-induced temporary state of 
relative NMDA receptor hypofunction (for details, refer to the investigator’s brochure [IB]). In 
addition, SAGE-718 has been shown to improve cognition in other neurodegenerative disorders 
(for details refer to the IB). The potential benefit of SAGE-718 is coupled with low risk of 
NMDA receptor-associated excitotoxicity, as SAGE-718 does not directly activate the NMDA 
receptor and thus is not expected to cause NMDA receptor associated glutamatergic 
excitotoxicity.  
SAGE-718 has been well characterized in a comprehensive series of in vitro and in vivo 
nonclinical studies that have defined its key pharmacology, absorption, distribution, metabolism, 
and excretion (ADME), drug-drug interaction, and toxicology findings, including 
compound-related effects and the reversibility of these changes. In a radiolabeled rat ADME 
study, there was no selective distribution or retention of radioactive SAGE-718 to pigmented 
tissues and no quantifiable concentration of radioactivity was observed in the eye lens in Long 
Evans rats, implying that potential risk of phototoxicity is low. 
Due to an unexplained mortality early in the 14-day oral repeat-dose rat study at 30 mg/kg/day, a 
human maximum concentration (Cmax) cap for clinical studies was established from the Day 0 
mean Cmax (443 ng/mL) in female rats at the 15 mg/kg/day dose level. A 10-fold safety factor 
was used to derive the 45 ng/mL clinical exposure cap (see Section 5.2). Across the nonclinical 
studies conducted with rats and dogs, a Cmax threshold for observation of convulsions occurred at 
exposures 20 to 40 times greater than clinically relevant exposures. 
Two Good Laboratory Practice (GLP) chronic toxicology studies (6 and 9 months) were 
conducted in rats and dogs, respectively, in adherence to International Conference on 
Harmonization (ICH) M3(R2) guidance. The exposure levels following repeated oral dose 
administration of SAGE-718 at the no-observed-adverse-effect level represent approximately 
15-fold to 45-fold higher (Cmax) median exposures than would be expected in humans after 
84 days of chronic dosing of 0.9 mg, as predicted by population PK models (for details, refer to 
the IB).  
Two GLP embryo-fetal development studies in rats and rabbits were conducted in adherence to 
ICH S5(R3).  There were no SAGE-718-related effects on maternal survival, clinical 
observations, mean maternal body weights, body weight gains, gravid uterine weights, food 
consumption, intrauterine growth, fetal survival, or fetal morphology (for details, refer to the IB).  
In a GLP fertility study in female rats conducted in adherence to ICH S5(R3), there were no 
SAGE-718-related effects on estrous cyclicity, reproductive performance (including mating, 
fertility, and pregnancy indices), or precoital interval length at any dose level. There were no 
SAGE-718-related macroscopic findings or alterations in organ weights. In a GLP fertility study 
in male rats conducted in adherence to ICH S5(R3), body weight, body weight gains, food 

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7.1.3.1. 
Additional visits related to the transition from Protocol Version 2 to Protocol 
Version 3 
Participants who have completed Day 395 under Protocol Version 2 (“718-CIH-301 v2 
Completers”) 
Participants who have completed their Day 395 visit under Protocol Version 2 and wish to 
continue participation under Protocol Version 3 or higher (“718-CIH-301 v2 Completers”) will 
return to the site for a Re-Qualification Visit (Table 4) up to 28 days prior to resuming IP at their 
Next Scheduled Study Treatment Visit (relative to the date of their Day 1 visit, see Table 5). 
Participants must sign an ICF for Protocol Version 3 or higher prior to any further study 
procedures. Inclusion criteria #1-11 (Section 8.1) and exclusion criteria #1-17 and #20-22 
(Section 8.2) will be re-confirmed at this visit and documented appropriately. Exclusion criteria 
#17 should be re-confirmed for both Cohort 1 and Cohort 2 participants. Exclusion criteria #2, 
#5, and #8 should be assessed at or relative to the time of the Re-Qualification Visit. Exclusion 
criteria #21 should be assessed relative to initial participation in 718-CIH-301 under Protocol 
Version 2 or prior.  
718-CIH-301 v2 Completers will resume IP at their Next Scheduled Study Treatment Visit (see 
Table 5). The Next Scheduled Study Treatment Visit may be any visit within the Treatment 
Period and will depend on the participant’s visit schedule, which will remain relative to the date 
of their Day 1 visit. 
Thirty (30) days after resuming IP at their Next Scheduled Study Treatment Visit (Table 5), 
718-CIH-301 v2 Completers will return to the site for a Post Re-Qualification Safety Check-in 
visit to evaluate safety (Table 4).  
For 718-CIH-301 v2 Completers, interim medical history will be collected from the time of 
completion of Day 395 under 718-CIH-301 Protocol Version 2 through informed consent for 
718-CIH-301 Protocol Version 3 or higher, AEs/SAEs will be collected from the time of 
informed consent for 718-CIH-301 Protocol Version 3 or higher through end of study 
participation, and prior and concomitant medications and procedures/therapies will be collected 
from the time of completion of Day 395 under 718-CIH-301 Protocol Version 2 through end of 
study participation. Documented ongoing AEs/SAEs and prior and concomitant medications and 
procedures/therapies from participation under 718-CIH-301 Protocol Version 2 or prior will be 
followed for resolution through end of study participation. 
Participants who have completed Day 365 but not Day 395 under Protocol Version 2 
Participants who have completed their Day 365 visit but not their Day 395 visit under Protocol 
Version 2 when Protocol Version 3 or higher is implemented will NOT be considered 
"718-CIH-301 v2 Completers". Instead, these participants will return to the site as soon as 
possible for a Study Continuation Visit (Appendix 2, Section 20.2) at which they will consent to 
Protocol Version 3 or higher, complete safety assessments, and be dispensed SAGE-718 to 
resume study treatment. They will continue study visits per Table 5 and will not have a Day 395 
visit.  
7.1.3.2. 
Remote Visits 
After the second year of the Treatment Period (ie, after the Month 24 visit), participants will be 
contacted by site staff periodically for remote visits, as indicated in Table 5. Participants will 

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8. 
SELECTION AND WITHDRAWAL OF PARTICIPANTS 
8.1. 
Participant Inclusion Criteria 
Participants must meet all the following criteria to qualify for participation in this study: 
For all participants: 
1. Completed 718-CIH-201 or 718-CIH-202 studies or meet eligibility criteria 
for the de novo cohort. 
2. Be capable of providing informed consent in the opinion of the investigator 
(all cohorts) or be willing to have a legally authorized representative 
provide informed consent on their behalf (for 718-CIH-201 or 
718-CIH-202 completers only). 
3. Have signed (or a legally authorized representative has signed, if 
applicable) an informed consent form prior to any study-specific 
procedures being performed.  
4. Agree to adhere to the study requirements. 
5. Be capable of complying with study procedures, in the opinion of the 
investigator. 
6. Be willing to invite a study partner, if available, who is reliable, competent, 
and at least 18 years of age to participate in the study. 
7. Be able to travel to the study center, and, judged by the investigator, is 
likely to be able to continue to travel to the study center to complete study 
visits for the duration of the study. 
8. [Revised in protocol version 3.0] 
8.A. Agree, if female, to use at least one method of highly effective 
contraception (refer to Section 9.2.4 for further details on acceptable 
forms of contraception) during participation in the study and for 30 days 
following the last dose of IP, unless she is postmenopausal (defined as no 
menses for 12 months without an alternative medical cause and 
confirmed by follicle-stimulating hormone > 40 mIU/mL), permanently 
sterile, or does not engage in sexual relations which carry a risk of 
pregnancy.  
9. [Revised in protocol version 3.0] 
9.A. Agree, if male, to use an acceptable method of effective contraception for 
the duration of study and for 21 days after receiving the last dose of IP, 
unless the participant does not engage in sexual relations which carry a 
risk of pregnancy. Acceptable methods of effective contraception are 
listed in Section 9.2.4. 
10. [Revised in protocol version 3.0] 
10.A. Agree, if male, to abstain from sperm donation during the treatment 
period and for 21 days after receiving the last dose of IP. 
11. Agree to refrain from drugs of abuse for the duration of the study and from 
alcohol during the 48 hours preceding each study visit. 

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Additional inclusion criteria for the de novo cohort (Cohort 3) 
12. Be at least 25 years old, but not older than 65 years of age at Screening. 
13. Meet all of the following criteria for HD: 
a. Genetically confirmed disease with CAG expansion ≥40 
b. No features of juvenile HD  
c. CAG-Age-Product (CAP) score ≥90, as calculated using the CAP formula: 
AGE × (CAG – 30) / 6.49. 
14. [Revised in protocol version 3.0] 
14.A. At Screening, scores of EITHER 
a. UHDRS-TFC=13 and MoCA ≤25,  OR 
b. UHDRS-TFC ≤12 and MoCA >25 
15. Completion of HD-CAB Trail Making-B Test in <240 seconds at Screening (Days -28 
to -1). 
8.2. 
Participant Exclusion Criteria 
Participants who meet any of the following criteria are disqualified from participation in this 
study: 
For all participants 
1. Have a diagnosis of an ongoing neurodegenerative condition other than HD, including 
but not limited to, Alzheimer’s Disease, vascular dementia, dementia with Lewy bodies, 
or Parkinson’s Disease. 
2. Have been diagnosed with and/or treated for any type of cancer (except successfully 
treated, locally excised basal cell carcinoma and melanoma in situ) within the past year 
prior to screening. 
3. Had gastric bypass surgery, have a gastric sleeve or lap band, or have had any related 
procedures that interfere with gastrointestinal transit. 
4. Plan to undergo elective surgery during participation in the study. 
5. Receive any of the following prohibited medications within 30 days of screening and 
during participation in the study: 
a. Medications with potent effects at the NMDA receptor, including amantadine, 
memantine, ketamine, cycloserine, or related compounds. 
b. Medications that inhibit cholesterol absorption (eg, ezetimibe). 
c. Bile acid sequestrants (eg, colesevelam, colestipol, cholestyramine). 
d. Other medications given at doses or in combinations that are likely to have a 
deleterious effect on cognitive performance, as determined by the investigator. 
e. Tetrahydrocannabinol (THC)-containing substances (any route of administration), 
regardless of whether they are prescribed. 
6. Take any psychotropic medications, including antidepressants and anxiolytics, unless the 
dose and frequency have been stable for at least 30 days prior to the first IP 
administration and are expected to remain stable for the duration of the study. 

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7. Have an ongoing medical or psychiatric condition that, in the opinion of the investigator, 
may compromise the participant’s safety or compliance with study requirements. 
8. Have supine vital signs outside of the following ranges at Screening or Baseline (vital 
sign measurements may be repeated once per visit for initial values outside these ranges): 
a. Heart rate <50 or >100 bpm, 
b. Systolic blood pressure <100 or >160 mmHg, 
c. Diastolic blood pressure <60 or >100 mmHg. 
9. Have an alcohol or drug use disorder within the past 2 years, as assessed by the 
investigator. A positive urine drug screen is exclusionary unless deemed by the 
investigator to reflect a prescribed medication. 
10. Have a history of significant hand injury that would preclude either writing or rapid 
bimanual computerized responding. 
11. Have a history of seizures or epilepsy, with the exception of a single episode of febrile 
seizures in childhood. 
12. Have a history of brain surgery, a significant head injury causing loss of consciousness 
greater than 30 minutes, or hospitalization due to a brain injury. 
13. Have a history, presence, and/or current evidence of intracranial abnormality (eg, stroke, 
hemorrhage, space-occupying lesion). 
14. Have a positive pregnancy test, be pregnant, be lactating, or intend to breast feed during 
the study. 
15. Be investigative site personnel, sponsor personnel, or an immediate member of their 
family (spouse, parent, child, or sibling whether biological or legally adopted). 
16. Is known to be allergic to any of SAGE-718 excipients, including soy lecithin. 
Additional exclusion criteria for 718-CIH-201/202 completers who enroll after a gap of >7 days 
since completion of the parent study (Cohort 2) and for the de novo cohort (Cohort 3): 
17. Have a history, presence, and/or current evidence of serologic positive results for human 
immunodeficiency virus (HIV)-1/HIV-2 or hepatitis B or hepatitis C. 
Additional exclusion criteria for the de novo cohort (Cohort 3): 
18. Have previous exposure to gene therapy, or have participated in any other HD 
investigational drug, biologic, or device trial within 180 days or a non-HD drug, biologic 
or device trial within 30 days or 5 half-lives (whichever is longer). Participants with 
confirmation of enrollment in the placebo arm of these investigational trials would not be 
excluded. Additionally, participants who have received treatment with antisense 
oligonucleotides or an mRNA splicing modifier will be excluded. 
19. Have current or recent suicidality, defined as follows: 
a. Suicidal ideation within the past month, as evidenced by a “Yes” on question 4 
(active suicidal ideation with some intent to act, without specific plan) or question 5 
(active suicidal ideation with specific plan and intent) on the ‘suicidal ideation’ items 
on the C-SSRS. 

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b. Suicidal behavior within the past year, as evidenced by a "Yes" on any of the 
C-SSRS Suicidal Behavior items on the C-SSRS. 
c. Presenting a serious risk of suicide in the opinion of the investigator. 
Additional exclusion criteria for 718-CIH-201/202 completers (Cohorts 1 and 2): 
20. Have current or recent suicidality, defined as follows: 
a. Suicidal ideation since last visit, as evidenced by a “Yes” on question 4 (active 
suicidal ideation with some intent to act, without specific plan) or question 5 (active 
suicidal ideation with specific plan and intent) on the C-SSRS. 
b. Suicidal behavior since last visit, as evidenced by a "Yes" on any of the CSSRS 
Suicidal Behavior items on the C-SSRS. 
c. Presenting a serious risk of suicide in the opinion of the investigator. 
21. Have one or more ongoing SAEs from the parent study that was assessed as related to IP. 
22. Have ongoing, unresolved AE(s), which in the opinion of the investigator or sponsor, is 
likely to interfere with study conduct or compliance. 
8.3. 
Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently assigned to study intervention/entered in the study. A minimal set of screen 
failure information will be collected, including demography, screen failure details, eligibility 
criteria, and any AE or SAE. 
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened once, with the approval of the medical monitor. Rescreened participants will be 
assigned a new participant number. 
8.4. 
Investigational Product Discontinuation and Early Termination from 
the Study 
A participant may withdraw from the study at any time at his/her own request for any reason. 
The investigator may discontinue a participant from the study and/or from IP for safety, 
behavioral, compliance, administrative reasons, or due to pregnancy. Any necessary interruptions 
to dosing of IP (eg, surgery) will be handled on a case-by-case basis. 
The reason for early termination (ET) from the study must be documented in the participant’s 
study record and recorded in the participant’s electronic case report form (eCRF).  
The Investigator must notify the sponsor and/or the medical monitor when a participant stops 
participation in the study for any reason.  
Participants who discontinue IP early will be invited by the investigator to complete an early 
termination (ET) visit within 7 days of IP discontinuation and will be asked to return to the clinic 
for a Safety Follow-Up Visit 30 days (±7 days) after the ET visit, if possible. The participant will 
be permanently discontinued from IP (if not previously discontinued) at the ET visit and from 
the study at the Safety Follow-Up Visit. If the participant does not complete a Safety Follow-Up 
Visit, they will be permanently discontinued from the study at the ET visit. The Safety Follow-
Up Visit will be used to assess AEs and concomitant medications or procedures/therapies; 

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participants will undergo a urine pregnancy test (females of childbearing potential [FOCBP] 
only), physical examination, vital signs, C SSRS, 
.   
If the participant withdraws consent for disclosure of future information, the sponsor will retain 
and continue to use any data collected before such a withdrawal of consent. 
If a participant withdraws from the study, he/she may request destruction of any samples taken 
and not tested, and the investigator must document this in the site study records. 
Possible reasons for study discontinuation include but are not limited to the following:  
• AE 
• Pregnancy 
• Protocol deviation 
• Non-compliance with study drug 
• Lost to follow-up 
• Withdrawal by subject 
• Screen failure 
• Study terminated by sponsor 
• Physician decision 
• Other 
8.4.1. 
Loss to Follow-up 
A participant will be deemed lost to follow-up after at least 3 attempts at contacting the 
participant have been made and it has been at least 1 month since the last participant contact. All 
attempts at contact and the reason for discontinuation will be documented. If the investigator 
becomes aware of a change in the participant’s status or receives more information about a 
participant’s disposition, this information will be documented.  
8.4.2. 
Replacement of Participants 
Participants who discontinue or withdraw from the study will not be replaced. However, 
additional participants may be enrolled in the de novo cohort if the early discontinuation rate is 
higher than expected. 

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9. 
TREATMENT OF PARTICIPANTS 
9.1. 
Description of Investigational Product 
SAGE-718 oral softgel lipid capsules are opaque, white to off-white, oval capsules containing 
0.9 mg of SAGE-718 drug substance. 
9.2. 
Prior Medications, Concomitant Medications, Restrictions, and 
Contraception Requirements 
9.2.1. 
Prior and Concomitant Medications, Supplements, and Procedures/Therapies 
All medications, supplements, procedures, and therapies taken within 8 weeks prior to obtaining 
718-CIH-301 informed consent will be recorded through the end of the study.  
All medications, supplements, procedures, and therapies used to treat Huntington's Disease or to 
treat or prevent COVID, regardless of timing will be recorded through the end of the 
718-CIH-301 study.  
Because this study aims to measure effects on cognitive performance, it is important to evaluate 
single or combined concomitant medications and their doses for their potential effects on 
cognition. Investigators will carefully review concomitant medications for possible cognitive 
effects at Screening to determine participant eligibility and throughout the study. 
9.2.2. 
Prohibited Medications 
Prohibited medications prior to and during the study include: 
• Exposure to gene therapy previously or anytime during the study  
• Treatment with any other HD investigational drug, biologic, or device trial within 
180 days prior to Screening and until the final visit 
• Treatment with any non-HD investigational drug, biologic, or device trial within 
30 days or 5 half-lives (whichever is longer) prior to Screening and until the final 
visit 
• For the de novo cohort only: Treatment with antisense oligonucleotides or an mRNA 
splicing modifier previously or anytime during the study 
Use of the following medications is prohibited during the entire course of the study: 
• Medications that inhibit cholesterol absorption (eg, ezetimibe). 
• Bile acid sequestrants (eg, colesevelam, colestipol, cholestyramine). 
• Medications with potent effects at the NMDA receptor, including memantine, 
amantadine, cycloserine, ketamine, or related compounds. 
• THC-containing substances (any route of administration), regardless of whether or 
not they are prescribed. 
Any medication determined necessary for the welfare of the participant may be given at the 
discretion of the investigator at any time during the study. If possible, the PI should inform the 

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medical monitor about the use of any prohibited medications.  However, the use of any 
prohibited medications will be captured as a protocol deviation.   
9.2.3. 
Other Restrictions and Recommendations 
Participants must agree to refrain from drugs of abuse for the duration of the study (unless 
deemed by the investigator to reflect a prescribed medication) and from alcohol during the 
48 hours preceding each study visit. 
Psychotropic medications, including antidepressants and anxiolytics, must be at a stable dose for 
at least 30 days prior to the first IP administration. Additions and/or modifications to these 
medications should be minimized throughout the course of the study. 
Adjustment and/or addition of medications that are known to affect cognitive performance 
(eg, stimulants, benzodiazepines, antipsychotics, anticholinergics) is to be avoided as much as 
possible.  
Other medications given at doses, frequencies, or in combinations that are likely, in the opinion 
of the investigator, to have a deleterious effect on cognitive performance are to be avoided as 
much as possible. 
9.2.4. 
Acceptable Forms of Contraception 
As per the Clinical Trials Facilitation and Coordination Group (CTFG), a female is considered of 
childbearing potential (FOCBP) ie, 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 and confirmed by follicle-stimulating hormone [FSH] >40 mIU/mL. A high follicle 
stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a 
postmenopausal state in females not using hormonal contraception or hormonal replacement 
therapy. However, in the absence of 12 months of amenorrhea, a single FSH measurement is 
insufficient.  
A male is considered fertile after puberty unless permanently sterile by bilateral orchidectomy. 
Acceptable forms of highly effective contraception (ie, can achieve a failure rate of <1% per year 
when used consistently and correctly) for participants of childbearing potential or for a male 
participant’s partner of childbearing potential include: 
• Sexual abstinence; 
• Combined (estrogen and progestogen containing) oral, intravaginal, or transdermal 
hormonal contraception associated with inhibition of ovulation; 
• Oral, injectable, or implantable progestogen-only hormonal contraception associated 
with inhibition of ovulation;  
• Intrauterine device; 
• Intrauterine hormone-releasing system; 

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10. 
INVESTIGATIONAL PRODUCT MATERIALS AND 
MANAGEMENT 
10.1. 
Investigational Product 
SAGE-718 softgel lipid capsules are opaque, white to off-white, oval capsules containing 0.9 mg 
of SAGE-718 drug substance. The capsules are composed of SAGE-718 drug substance and 
butylated hydroxyanisole, gelatin, glycerin, glyceryl monocaprylate, glyceryl monolinoleate, 
lecithin, medium chain triglycerides, purified water, sorbitol, titanium dioxide, and vitamin E 
polyethylene glycol succinate as excipients.  
Table 8: 
Investigational Product 
Product Name: 
SAGE-718 0.9 mg  
Dosage Form: 
Softgel lipid capsule 
Unit Dose 
0.9 mg 
Route of Administration 
Oral 
Physical Description 
Opaque, white to off-white, oval, softgel lipid capsule 
Manufacturer 
 
 
10.2. 
Investigational Product Packaging and Labeling 
SAGE-718 oral softgel lipid capsules are packaged in blisters using ACLAR® rigid barrier film 
and heat sealable foil lidding with an additional child resistant lid (refer to the pharmacy manual 
for further details).  
The composition and pharmaceutical quality of the oral softgel lipid capsule will be maintained 
according to current Good Manufacturing Practice (GMP). Labels with all required information 
and conforming to all applicable Code of Federal Regulations and GMP/Good Clinical Practice 
(GCP) guidelines and all other applicable regulations will be prepared by Sage.  
10.3. 
Investigational Product Storage 
Upon receipt of the IP, the investigator, or the responsible pharmacist or designee, will inspect 
the product and acknowledge receipt in accordance with the study-specific process.  
The IP must be carefully stored at the temperature specified in the IB and in the Pharmacy 
Manual, securely and separately from other drugs. The IP may not be used for any purpose other 
than the present study. After the study is completed, all unused IP must be returned per the 
sponsor’s instructions or destroyed locally per the site’s procedure(s).  
The Investigator or designee will be responsible for ensuring appropriate storage, compounding 
(if applicable), dispensing, inventory, and accountability of the IP. An accurate, timely record of 
the disposition of the IP must be maintained.  

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10.4. 
Investigational Product Preparation 
Beginning at the Day 1 visit and continuing throughout the Treatment Period, an adequate supply 
of SAGE-718 0.9 mg will be provided as an oral softgel lipid capsule for self-administration 
once daily in the morning. 
10.5. 
Investigational Product Administration 
Each 0.9 mg dose of IP will be self-administered once daily in the morning.  
Participants are to swallow the capsule whole with approximately 240 mL (8 fluid ounces) of 
water. For doses taken in the clinic, site staff will watch the participant self-administer the IP. 
The SAGE-718 0.9 mg softgel lipid capsule will be self-administered by participants once daily 
in the morning. Sites will dispense a sufficient supply of IP to the participants to take at home 
with instructions for use until their next visit (refer to Table 2, Table 3, and Table 5).  
This study will use a medication adherence monitoring platform for all participants in the study. 
Built-in reminders and a communication system allow real-time intervention in case of missed 
doses. Use of the platform is required for all participants in the study to reinforce the proper 
dosing schedule and improve data integrity (Section 10.5.1). The AiCure platform is compliant 
with all applicable privacy and data security laws; data is captured, processed, and analyzed in a 
compliant manner as outlined in each local ICF. 
In addition, the participant will be instructed to bring their dosing kit to the site as outlined in 
Table 2, Table 3, and Table 5. All participants should be reinstructed about the dosing 
requirement during study contacts. The authorized study personnel conducting the re-education 
must document the process in the participant source records.  
The investigator(s) will record any reasons for noncompliance in the source documents.  
A third-party courier will ship IP from the site to the homes of the participants for Months 27, 
33, 39, and 45, as specified in the Pharmacy Manual. 
10.5.1. 
Medication Adherence and Reminder System 
10.5.1.1. Registration in the AiCure platform 
The platform may be downloaded as an app on the participant’s personal smartphone. If a 
participant does not own a smartphone or prefers not to use his/her personal smartphone, one of 
the backup provisioned devices should be provided.  
• Participants will be registered in the platform. 
• Participant training is automated within the application.  
10.5.1.2. Ongoing Use and Monitoring of Medication Adherence  
Participants should use the application to record each intake of study medication throughout the 
trial, both at home between visits and during the visits when study drug is taken at the site.  
Site personnel should regularly check the dashboard to ensure consistent medication adherence 
throughout the study. In cases of missed doses or pending data, site personnel should follow up 
with the participant as soon as possible to assess the reason for nonadherence and reinforce the 

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importance of complying with the study drug dosing schedule. If the participant reports that a 
dose was taken but not logged in the app, site personnel should reclassify this dose to “site 
reported” using the dashboard.  
Participants who are consistently noncompliant with study medication should be discussed with 
the medical monitor. 
10.6. 
Investigational Product Accountability, Handling, and Disposal 
Upon receipt of IP, the investigator(s), or the responsible pharmacist or designee, will inspect the 
IP and complete and follow the instructions regarding receipt and storage in the IB and (where 
applicable) in the Pharmacy Manual. A copy of the shipping documentation will be kept in the 
study files. 
The designated site staff will dispense the supplied participant-specific kits to participants at the 
planned dispensation visit intervals outlined in Table 2, Table 3, and Table 5. 
The IP provided is for use only as directed in this protocol. The investigator or designee must 
keep a record of all IP received, used, and returned/discarded.  
Sage will be permitted access to the study supplies at any time with appropriate notice during or 
after completion of the study to perform drug accountability reconciliation.  
The investigator, pharmacist, or qualified designee is responsible for drug accountability, 
reconciliation, and record maintenance (ie, receipt, reconciliation, and final disposition records). 
At the end of the study, any unused IP will be returned to Sage for destruction or destroyed 
locally per the site’s procedures; disposition of IP will be documented. 
10.7. 
Product Complaints 
A product complaint is any written, electronic, or verbal expression of dissatisfaction regarding 
the identity, quality, reliability, safety, purity, potency, effectiveness, or performance (applicable 
for approved marketed products) of a drug product after it is released for distribution.  
In the course of conduct of the study, study personnel may become aware of a product complaint 
associated with the use of a Sage product. Personnel shall notify Sage within 24 hours by 
forwarding the product complaint information via the contact information listed in Table 1. 
Where possible, personnel should segregate and retain any product, materials, or packaging 
associated with the product complaint until further instruction is provided by Sage or its 
designated representative(s). 

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12. 
SAFETY ASSESSMENTS 
12.1. 
Safety Parameters 
All assessments will be conducted according to the Schedules of Assessments (Table 2, Table 3, 
Table 4, and Table 5) 
 
.  
Abnormalities in physical examinations, vital signs, ECG, and out of range values in laboratory 
test results will be interpreted by an investigator as clinically significant (CS) or not clinically 
significant (NCS) in the source documents.  
AEs, or prior/concomitant medications and procedures/therapies from the parent studies will be 
collected in 718-CIH-301 according to the eCRF Completion Guidelines. 
12.1.1. 
Demography and Medical History 
Demographic characteristics (including age, race, sex, ethnicity, years of education, years of 
employment and current employment status) and a full medical history will be documented for 
all cohorts. Parent study demographic characteristics data will be carried over from the parent 
study for rollover participants, if not specifically collected in 718-CIH-301. Prior participation in 
718-CIH-201 and 718-CIH-202 will be collected. 
Medical history will be carried over from the corresponding parent studies 718-CIH-201/202 for 
all rollover participants. Any medical history from the end of the parent study through informed 
consent for 718-CIH-301 will also be collected via the medical history eCRF. Any resolved AEs 
from parent study will be included in the medical history eCRF if clinically relevant. 
For 718-CIH-301 v2 Completers, interim medical history will be collected from the time of 
completion of Day 395 under 718-CIH-301 Protocol Version 2 through informed consent for 
718-CIH-301 Protocol Version 3 or higher. 
History of HD (for participant and family) will be collected separately. 
12.1.2. 
Weight and Height 
Height will be measured for de novo participants only. For the rollover participants, the 
preceding height measurement results will be carried over from the corresponding parent studies 
718-CIH-201 and 718-CIH-202. Height will also be measured at the Re-Qualification Visit 
(Table 4) for 718-CIH-301 v2 Completers. 
Weight will be measured in all participants and documented. Body mass index will be calculated.  
12.1.3. 
Physical Examination 
Whenever possible, the same individual should perform all physical examinations.  
A full physical and neurological examination is to be conducted during Screening for de novo 
and gap rollover participants and carried over from the parent study for direct rollover 
participants, and Days 180 for all participants. A full physical and neurological examination will 
also be done at the Re-Qualification Visit (Table 4) for 718-CIH-301 v2 Completers. At other 
visits (refer to Table 2, Table 3, and Table 5), physical examinations will include a brief 

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assessment of general appearance, cardiovascular, respiratory, gastrointestinal, and neurological 
systems and followed by a targeted physical assessment as needed. An unscheduled, symptom-
directed examination may be conducted at any time at the discretion of the investigator.  
Any abnormality in physical examinations will be interpreted by the investigator as abnormal, 
NCS, or abnormal, CS, in source documents. Any CS finding in physical examination will be 
reported as an AE. 
12.1.4. 
Vital Signs 
Vital signs include body temperature, respiratory rate, heart rate, and blood pressure. On dosing 
days, vital signs will be measured prior to dosing. Blood pressure and heart rate will be measured 
after the participant has been in the supine position for at least 5 minutes and then repeated 
approximately 1 and 3 minutes after standing at all scheduled time points. Vital signs can be 
repeated once per visit if out of range. 
Any abnormality in vital signs will be interpreted by an investigator as abnormal, NCS; or 
abnormal, CS in source documents. Changes from baseline in vital signs are considered AEs if 
they result in discontinuation or interruption of IP, require therapeutic medical intervention, meet 
protocol specific criteria (if applicable) or if the investigator considers them to be CS. Changes 
from baseline in vital signs that are clearly attributable to another AE do not require discrete 
reporting. 
12.1.5. 
Electrocardiogram  
A 12-lead ECG will be performed at the time points described in Table 2, Table 3, Table 4, and 
Table 5. At each time point, a single ECG will be recorded. The standard intervals (heart rate, 
PR, QRS, QT, and QT corrected according to Fridericia’s formula [QTcF]) as well as any 
rhythm abnormalities will be recorded. 
ECGs will be performed after the participant has been resting in a supine position for at least 
5 minutes. When ECG measurements coincide with safety assessments, vital signs assessment or 
blood draws, blood draws should be carried out after ECG and vital signs. 
Any abnormality in ECG will be interpreted by an investigator as abnormal, NCS; or abnormal, 
CS in source documents. Changes from baseline in ECGs are considered AEs if they result in 
discontinuation or interruption of IP, require therapeutic medical intervention, meet protocol 
specific criteria (if applicable) or if the investigator considers them to be CS. Changes from 
baseline in ECGs that are clearly attributable to another AE do not require discrete reporting. 
12.1.6. 
Laboratory Assessments 
Blood and urine samples for clinical laboratory assessments will be collected. Analytes to be 
evaluated are summarized in Table 9. 

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Table 9: 
Summary of Clinical Laboratory Analytes 
Biochemistry 
Renal Panel: glucose, calcium, phosphorus, blood urea nitrogen, 
creatinine, sodium, potassium, chloride, bicarbonate 
Hepatic Panel: albumin, alanine aminotransferase, alkaline phosphatase, 
aspartate aminotransferase, total bilirubin, direct bilirubin, indirect 
bilirubin, total protein, lactate dehydrogenase, gamma glutamyl 
transferase 
Other: triglycerides, cholesterol (low density lipoprotein [LDL], high 
density lipoprotein [HDL]), creatine phosphokinase, TSH and reflex to 
free T3/T4 if TSH is abnormal 
Hematology 
Red blood cell (RBC) count, hemoglobin, hematocrit, white blood cell 
count with differential, platelet count, RBC indices (mean corpuscular 
volume [MCV], mean corpuscular hemoglobin [MCH], and mean 
corpuscular hemoglobin concentration [MCHC]).  
Urinalysis 
Protein, glucose, pH, blood, leukocyte esterase, urobilinogen, bilirubin, 
ketones, nitrite 
Coagulation 
Activated partial thromboplastin time, prothrombin time, and 
international normalized ratio 
Serology (screening only 
for Cohort 2 and 3; 
re-qualification for 
718-CIH-301 v2 
Completers) 
Hepatitis B and C screening tests, HIV-1 and -2 antibody 
Genetic test (screening 
only) 
CAG testa 
a 
De novo participants only. Genetically confirmed disease with CAG expansion ≥36 (for de novo: ≥40) collected 
as part of medical history is acceptable in lieu of central laboratory confirmation. For any genetic counseling, 
the study sites should follow their local practice.  
 
All clinical laboratory test results outside the reference range will be interpreted by the 
Investigator as abnormal, NCS; or abnormal, CS in source documents. Laboratory abnormalities 
are considered AEs if they result in discontinuation or interruption of IP, require therapeutic 
medical intervention, meet protocol specific criteria (if applicable) or if the investigator 
considers them to be CS. Laboratory abnormalities that are clearly attributable to another AE do 
not require discrete reporting. 
Serum FSH test will be conducted at Screening for the de novo female participants and rollover 
participants who are not surgically sterile and who have ≥12 months of spontaneous amenorrhea 
to confirm postmenopausal state as defined in this protocol. For the postmenopausal rollover 
participants (where postmenopausal state was confirmed in parent studies), the preceding FSH 
results will be carried over from the corresponding parent studies, 718-CIH-201/202, as 
applicable. 

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12.2. 
Adverse and Serious Adverse Events 
12.2.1. 
Adverse Event Definition 
An AE is any untoward medical occurrence in a patient or clinical investigation participant 
administered a pharmaceutical product and that does not necessarily have a causal relationship 
with this treatment. An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom or disease temporally associated with the use of a 
medicinal (investigational) product whether or not related to the medicinal (investigational) 
product. In clinical studies, an AE can include an undesirable medical condition occurring at any 
time, including baseline or washout periods, even if no study treatment has been administered. 
A TEAE is defined as an AE with onset after the start of IP, or any worsening of a pre-existing 
medical condition/AE with onset after the start of IP and throughout the study. The term IP 
includes any Sage IP, a comparator, or a placebo administered in a clinical study.  
Laboratory abnormalities and changes from baseline in vital signs, and ECGs are considered AEs 
if they result in discontinuation or interruption of IP, require therapeutic medical intervention, 
meet protocol specific criteria (if applicable) or if the investigator considers them to be CS. Any 
abnormalities that meet the criteria for an SAE should be reported in an expedited manner. 
Laboratory abnormalities and changes from baseline in vital signs and ECGs that are clearly 
attributable to another AE do not require discrete reporting (eg, electrolyte disturbances in the 
context of dehydration, chemistry, and hematologic disturbances in the context of sepsis). 
All AEs that occur after any participant has signed the informed consent and throughout the 
duration of the study, whether or not they are related to the study, must be reported to Sage. 
Participants who discontinue the IP due to an AE, regardless of investigator-determined 
causality, should be followed until the event is resolved, considered stable, or the investigator 
determines the event is no longer clinically significant. Any AEs that are unresolved at the 
participant’s last AE assessment in the study are followed up by the investigator for as long as 
medically indicated, but without further recording in the eCRF. The sponsor or its representative 
retains the right to request additional information for any patient with ongoing AE(s)/SAE(s) at 
the end of the study, if judged necessary. 
12.2.2. 
Serious Adverse Event Definition 
An SAE is any untoward medical occurrence that at any dose: 
• Results in death 
• Places the participant at immediate risk of death (a life-threatening event); however, 
this does not include an event that, had it occurred in a more severe form, might have 
caused death  
• Requires in-patient hospitalization or prolongation of existing hospitalization 
• Results in persistent or significant disability or incapacity 
• Results in a congenital abnormality or birth defect 
An SAE may also be any other medically important event that, in the opinion of the investigator 
may jeopardize the participant or may require medical intervention to prevent 1 of the outcomes 

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listed above (examples of such events include allergic bronchospasm requiring intensive 
treatment in an emergency room or convulsions occurring at home that do not require an 
inpatient hospitalization). 
SAEs that occur in the period after the end of participation of the parent study and prior to the 
participant signing the ICF will be recorded as medical history (if the SAE is assessed as not 
related to IP). All SAEs that occur after any participant has signed the ICF and throughout the 
duration of the study, whether or not they are related to the study, must be recorded on the SAE 
report form provided by Sage. Any SAE that is ongoing when the participant completes their 
final study visit, will be followed by the Investigator until the event has resolved, stabilized, 
returned to baseline status, or until the participant dies or is lost to follow up. 
A prescheduled or elective procedure or routinely scheduled treatment will not be considered an 
SAE, even if the participant is hospitalized. The site must document all the following: 
• The prescheduled or elective procedure or routinely scheduled treatment was 
scheduled (or on a waiting list to be scheduled) prior to obtaining the participant’s 
consent to participate in the study. 
• The condition requiring the prescheduled or elective procedure or routinely scheduled 
treatment was present before and did not worsen or progress, in the opinion of an 
investigator, between the participant’s consent to participate in the study and at the 
time of the procedure or treatment. 
12.2.3. 
Definition of Urgent Safety Measure and Unanticipated Problem  
In accordance with Article 10(b) of Directive 2001/20/EC, some reported events may result in an 
urgent safety measure (USM), defined as an action that the sponsor and investigator may take in 
order to protect the participants of a study against any immediate hazard to their health or safety. 
Examples of USMs include: 
• Suspension of enrollment due to significantly higher incidence of death at one site 
• Additional clinical or nonclinical investigations performed due to increased frequency 
of AEs 
• Halting a clinical study for safety reasons 
In accordance with FDA Guidance 21 Code of Federal Regulations (CFR) Part 312.66, some 
reported events may qualify as an unanticipated problem (UP), defined as any incident, 
experience, or outcome that meets all the following criteria: 
• Unexpected (in terms of nature, severity, or frequency) given (i) the research 
procedures that are described in the protocol-related documents, such as the 
IRB-approved research protocol and ICF; and (ii) the characteristics of the population 
being studied; related or possibly related to an individual’s participation in the study; 
and 
• Suggests the study may place the participant or others at a greater risk of harm 
(including physical, psychological, economic, or social harm) related to the study 
than was previously known or recognized. 

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Any UP must be reported within 24 hours of awareness via email to Sage and designee due to the 
urgent reporting requirements to regulators and IRB(s)/IECs(s). 
12.2.4. 
Relationship to Investigational Product 
The investigator must make the determination of relationship to the IP for each AE (not related, 
related). The following definitions should be considered when evaluating the relationship of AEs 
and SAEs to the IP.  
Not Related 
An AE will be considered “not related” to the use of the IP if there is not a reasonable 
possibility that the event has been caused by the IP. Factors pointing towards this 
assessment include but are not limited to: the lack of temporal relationship between 
administration of the IP and the event, the presence of biologically implausible 
relationship between the product and the AE, or the presence of a more likely 
alternative explanation for the AE 
Related 
An AE will be considered “related” to the use of the IP if there is a reasonable 
possibility that the event may have been caused by the product under investigation. 
Factors that point towards this assessment include but are not limited to: a positive 
rechallenge, a reasonable temporal sequence between administration of the drug and 
the event, a known response pattern of the suspected drug, improvement following 
discontinuation or dose reduction, a biologically plausible relationship between the 
drug and the AE, or a lack of alternative explanation for the AE 
 
12.2.5. 
Recording Adverse Events 
AEs spontaneously reported by the participant and/or in response to an open question from the 
study personnel or revealed by observation will be recorded during the study at the 
investigational site. The AE term should be reported in standard medical terminology when 
possible. For each AE, the investigator will evaluate and report the onset (date and time), 
resolution (date and time), intensity, causality, action taken, outcome and seriousness criteria (if 
applicable), and whether or not it caused the participant to discontinue the IP or withdraw early 
from the study. 
Intensity will be assessed according to the following scale: 
• Mild: symptom(s) barely noticeable to participant or does not make participant 
uncomfortable; does not influence performance or functioning; prescription drug not 
ordinarily needed for relief of symptom(s)  
• Moderate: symptom(s) of a sufficient severity to make participant uncomfortable; 
performance of daily activity is influenced; participant is able to continue in study; 
treatment for symptom(s) may be needed 
• Severe: symptom(s) cause severe discomfort; symptoms cause incapacitation or 
significant impact on participant’s daily life; severity may cause cessation of 
treatment with IP; treatment for symptom(s) may be given and/or participant 
hospitalized  

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It is important to distinguish between serious and severe AEs. Severity is a measure of intensity 
whereas seriousness is defined by the criteria under Section 12.2.2. An AE of severe intensity 
may not necessarily be considered serious. 
12.2.6. 
Reporting Serious Adverse Events 
In order to adhere to all applicable laws and regulations for reporting an SAE(s), the study site 
must notify Sage and designee within 24 hours of the study site staff becoming aware of the 
SAE(s). The investigator must complete, sign and date the SAE report form, verify the accuracy 
of the information recorded on the SAE report form with the corresponding source documents, 
and send a copy to Sage and designee.  
Additional follow-up information, if required or available, should all be sent to Sage and 
designee within 24 hours of receipt on a follow-up SAE report form and placed with the original 
SAE information and kept with the appropriate section of the eCRF and/or study file. 
Serious adverse events occurring after the designated follow-up time for the study, should be 
reported to Sage and designee according to the timelines noted above only if the investigator 
considers the SAE related to IP. 
Sage, or designee, is responsible for notifying the relevant regulatory authorities of certain 
events. It is the principal investigator’s responsibility to notify the IRB/IEC of all SAEs that 
occur at his or her site. Investigators will also be notified of all suspected unexpected serious 
adverse reactions (SUSARs) that occur during the clinical study. IRBs/IECs will be notified of 
SAEs and/or SUSARs as required by local law. 
12.2.7. 
Assessment of Liver Biochemistry for Hy’s Law Screening, or Hy’s Law 
Laboratory Criteria  
Hy’s Law is a principle outlining specific criteria to indicate when an individual is at high risk of 
a severe drug induced liver injury (DILI) as a result of incurring hepatocellular injury sufficient 
to impair bilirubin excretion.  
Potential Hy’s Law is defined as [(total bilirubin >2xULN) AND alkaline phosphatase <2xULN 
(any time post-baseline, measured at the same time point of assessment)] AND [(ALT or AST 
>3xULN) AND alkaline phosphatase <2xULN, any time post-baseline, measured at the same 
time point of assessment]. Hy’s Law criteria are met if there is no alternative explanation for the 
elevations in liver biochemistry other than DILI caused by the IP. The elevations of 
transaminases and bilirubin may occur together or at different time points during the study, 
therefore, to identify cases of potential Hy’s Law, a comprehensive review of liver biochemistry 
must be performed.  
The investigator is responsible for determining whether a participant meets potential Hy’s Law 
criteria at any point during the study. If a participant has elevations in liver biochemistry, further 
evaluation may be required and, if elevations meet the potential Hy’s Law criteria, it must be 
reported as an SAE within 24 hours of Investigator awareness (see Section 12.2.6 for procedure 
on reporting an SAE). All results of laboratory tests including alkaline phosphatase testing 
should also be appended to the SAE form. The investigator must continue to follow the 
participant until liver biochemistry returns to normal or baseline levels, or for as long as 

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clinically indicated. In addition, the investigator should perform any necessary diagnostic 
evaluations to investigate the etiology of the event and update the SAE report accordingly.  
These events must also be recorded as an SAE in the eCRF with the investigator’s assessment of 
seriousness, severity, and causality, and a detailed narrative must be provided on the SAE form. 
The investigator is responsible for recording data pertaining to potential Hy’s Law/Hy’s Law 
cases and for reporting AEs and SAEs in line with standard safety reporting procedures (see 
Section 12.2.5  and Section 12.2.6). 
IP dose modifications for participants who meet potential Hy’s Law criteria should be made 
according to Section 7.4.3. 
12.3. 
Pregnancy 
If a participant becomes pregnant after the first administration of IP, pregnancy information must 
be collected and recorded on the Pregnancy form and submitted to Sage and designee within 
24 hours of learning of the pregnancy. Details will be collected for all pregnancies for which 
conception was likely to have occurred after the start of IP administration until 5 terminal 
half-lives following the last administration of IP or until the completion of the study whichever is 
longer. Any pregnancy occurring in that time frame will be followed until delivery or 
termination of the pregnancy. The investigator will also attempt to collect pregnancy information 
on any participant’s partner who becomes pregnant after the participant has received the first 
administration of IP. After obtaining the necessary signed informed consent from the pregnant 
partner directly, the investigator will follow the same pregnancy reporting procedures specified 
for pregnant participants.  
The participant or participant’s partner will be followed to determine the outcome of the 
pregnancy. The outcome of all pregnancies (eg, spontaneous abortion, elective abortion, normal 
birth) must be followed and documented even if the participant was discontinued from the study. 
The investigator will collect follow-up information on the participant or participant’s partner and 
the neonate, and the information will be forwarded to Sage and designee within 24 hours of 
awareness. Generally, follow-up will not be required for longer than 6 to 8 weeks beyond the 
estimated delivery date. Any termination of pregnancy will be reported, regardless of fetal status 
(presence or absence of anomalies) or indication for the procedure. 
Pregnancy in itself is not regarded as an AE unless there is a suspicion that an IP may have 
interfered with the effectiveness of a contraceptive medication. Any complication during 
pregnancy (eg, anemia, infections, pre-eclampsia) should be reported as an AE/SAE. If the 
outcome of the pregnancy meets the criteria for immediate classification as an SAE 
(ie, spontaneous abortion, stillbirth, neonatal death), the investigator should follow the 
procedures for reporting an SAE (Section 12.2.6).  
The investigator will permanently withdraw the participant from IP if the participant becomes 
pregnant. 

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12.4. 
Special Considerations 
Drug abuse is the persistent or sporadic, intentional excessive use of IP which is accompanied by 
harmful physical or psychological effects in the participant. If an event of drug abuse occurs 
during the study, it must be reported to the sponsor and/or designee using the Special 
Considerations form within 24 hours of the site becoming aware of the event(s). If the drug 
abuse results in an AE or SAE, the AE or SAE must also be recorded and reported as described 
in Section 12.2.5 and Section 12.2.6, respectively. 
Drug misuse refers to situations where IP is intentionally and inappropriately used not in 
accordance with the intended use as specified in the protocol. If an event of drug misuse occurs 
during the study, it must be reported to the sponsor and/or designee using the Special 
Considerations form within 24 hours of the site becoming aware of the event(s). If the drug 
misuse results in an AE or a SAE, the AE or SAE must also be recorded and reported as 
described in Section 12.2.5  and Section 12.2.6, respectively. 
An overdose is any dose of study treatment given to a participant or taken by a participant that 
exceeds the dose described in the protocol. Overdoses are not considered AEs and should not be 
recorded as an AE on the CRF; however, all overdoses must be recorded on the Special 
Considerations Form and sent to Sage and designee within 24 hours of the site becoming aware 
of the overdose. An overdose must be reported to Sage and designee even if the overdose does 
not result in an AE. If an overdose results in an AE or SAE, the AE or SAE must be recorded 
and reported as described in Section 12.2.5 and Section 12.2.6, respectively.  
A medication error is any preventable event that may cause or lead to inappropriate medication 
use or participant harm while the medication is in the control of the healthcare professional, 
participant, or consumer. All medication errors must be recorded on the Special Considerations 
Form and sent to the sponsor and/or designee within 24 hours of the site becoming aware of the 
medication error. The medication error must be reported to the sponsor and/or designee even if 
the medication error does not result in an AE. If a medication error results in an AE, the AE must 
be recorded and reported as described in Section 12.2.5 and Section 12.2.6, respectively. 

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13.6.4. 
Vital Signs 
Vital sign results at each visit and mean changes from baseline will be summarized by scheduled 
visit. Potentially CS values will be summarized by cohort. Vital sign results will be listed by 
participant and timing of collection. 
13.6.5. 
12-Lead Electrocardiogram 
The following ECG parameters will be listed for each participant: heart rate, PR, QRS, QT, and 
QTcF. ECG data will be summarized by visit. Potentially CS values of QTcF will be 
summarized by cohort. ECG findings will be listed by participant and visit. 
13.6.6. 
Prior and Concomitant Medications 
Medications will be coded using World Health Organization-Drug dictionary March 2021, or 
later.  
All medications and supplements taken within 8 weeks prior to obtaining 718-CIH-301 ICF, all 
medications used to treat HD regardless of timing, and all nonpharmacological methods 
(eg, psychosocial, psychotherapeutic) used to treat or prevent neuropsychiatric, functional, and 
cognitive manifestations of HD will be recorded through the end of the 718-CIH-301 study, 
according to the eCRF Completion Guidelines. All medications and supplements taken or 
changed after signing ICF through the end of the study (including start and end dates, route, 
dose/units, frequency, and indication) will be recorded.  
For 718-CIH-301 v2 Completers, prior and concomitant medications and procedures/therapies 
will be collected from the time of completion of Day 395 under 718-CIH-301 Protocol Version 2 
through end of study participation. Documented ongoing prior and concomitant medications and 
procedures/therapies from participation under 718-CIH-301 Protocol Version 2 or prior will be 
followed for resolution through end of study participation. 
Medication taken prior to the initiation of the start of IP will be denoted “Prior”. Those 
medications taken prior to the initiation of the IP and continuing beyond the initiation of the IP 
or those medications started at the same time or after the initiation of the IP will be denoted 
“Concomitant”.  
Medications will be presented according to whether they are “Prior” or “Concomitant” as 
defined above. If medication dates are incomplete and it is not clear whether the medication was 
concomitant, it will be assumed to be concomitant.  
Details of prior and concomitant medications will be listed by participant.  
13.6.7. 
Columbia Suicide Severity Rating Scale 
Suicidality data collected on the C-SSRS at Baseline and by visit during the study period will be 
listed and summarized by cohort. Listings will include behavior type and/or category for Suicidal 
Ideation and Suicidal Behavior of the C-SSRS.  
13.6.8. 
 
 

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14. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
14.1. 
Study Monitoring 
Unless otherwise waived or addressed in another forum (eg, investigator meeting), before an 
investigational site can enter a participant into the study, a representative of Sage will visit the 
investigational study site to: 
• Confirm the adequacy of the facilities 
• Discuss with the investigator(s) and other personnel their responsibilities with regard 
to protocol adherence, IP management, GCP/ICH GCP compliance, and the 
responsibilities of Sage or its representatives. Agreed upon site responsibilities will be 
documented in a Clinical Trial Agreement between Sage and the investigator. 
During the study, a monitor from Sage 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 eCRF, and that IP accountability checks are being 
performed. 
• Perform source data verification. This includes a comparison of the data in the eCRF 
with the participant’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 
participant (eg, medical records, source documents, clinic charts). 
• Record and report any protocol deviations not previously sent to Sage. 
• Confirm AEs and SAEs have been properly documented on eCRFs and confirm any 
SAEs have been forwarded to Sage, and those SAEs that met criteria for reporting 
have been forwarded to the IRB or IEC. 
The monitor will be available between visits if the investigator(s) or other staff needs 
information or advice. 
14.2. 
Audits and Inspections 
Sage or authorized representatives of Sage, a regulatory authority, or an IRB/IEC may visit the 
site to perform an audit(s) or inspection(s), including source data verification. The purpose of a 
Sage audit or a regulatory authority inspection 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/ICH GCP 
guidelines, and any applicable regulatory requirements. The investigator should contact Sage 
immediately at InspectionNotification@sagerx.com if contacted by a regulatory agency or 
IRB/IEC about an inspection. 

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14.3. 
Institutional Review Board or Independent Ethics Committee 
The principal investigator must obtain IRB (or IEC) approval for the clinical study prior to 
enrolling a participant. Initial IRB (or IEC) approval, and all materials approved by the IRB (or 
IEC) for this study including the participant consent form and recruitment materials must be 
maintained by the investigator and made available for inspection. 

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15. 
QUALITY CONTROL AND QUALITY ASSURANCE 
To ensure compliance with GCP and all applicable regulatory requirements, Sage may conduct a 
quality assurance audit(s) at the clinical site. Please see Section 14.2 for more details regarding 
the audit process. 
The investigator must have adequate quality control practices to ensure that the study is 
performed in a manner consistent with the protocol, GCP/ICH GCP guidelines, and applicable 
regulatory requirements. The investigator is responsible for reviewing all identified protocol 
deviations. Protocol deviations that harm or increase the possibility of harm to the rights and 
welfare of a participant, or a deviation made without prior IRB/IEC approval to eliminate an 
immediate hazard to the participant should be reported to the IRB/IEC per the IRB/IEC’s written 
procedures. 
The investigator is responsible for supervising any individual or party to whom the investigator 
delegates study-related duties and functions conducted at the study site. When the investigator 
retains the services of any individual or party to perform study-related duties and functions, the 
investigator must ensure the individual or party is qualified to perform study-related duties and 
functions and should implement procedures to ensure the integrity of the study-related duties and 
functions performed, and any data generated. 
The investigator must maintain adequate and accurate source documents and study records that 
include all pertinent observations on each of the site’s study participants. Source data must be 
attributable, legible, contemporaneous, original, accurate, and complete. Changes to source data 
should be traceable, should not obscure the original entry, and should be explained, if necessary 
to provide clarification. 

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16. 
ETHICS 
16.1. 
Ethics Review 
The final study protocol, including the final version of the ICF, must be given a written and 
dated approval or favorable opinion by an IRB or IEC as appropriate. The investigator must 
obtain and document approval before he or she can enroll any participant into the study. The IRB 
or IEC must supply to the sponsor a list of the IRB/IEC membership and a statement to confirm 
that the IRB/IEC is organized and operates according to GCP and applicable laws and 
regulations. 
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 participants 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 IP. Sage 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. In addition, the principal investigator must 
inform the IRB/IEC and sponsor of any changes significantly affecting the conduct of the study 
and/or increasing the risk to participants (eg, violations to the protocol or urgent safety measures 
taken for participant safety). 
16.2. 
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 and GCP guidelines, as well as all 
applicable regional or national regulatory requirements. 
16.3. 
Written Informed Consent 
Prior to enrolling a study participant, the investigator(s) will ensure that the participant is given 
full and adequate oral and written information about the nature, purpose, possible risk and 
benefit of the study. Participants must also be notified that they are free to discontinue from the 
study at any time. The participant should be given the opportunity to ask questions and allowed 
time to consider the information provided. 
When the participant decides to participate in the study, the participant (or their legally 
authorized representative, if applicable, for 718-CIH-201/718-CIH-202 completers only) must 
provide signed and dated informed consent. The written consent must be obtained before 
conducting any study procedures. The investigator must document the consent process in the 
participant’s source documentation. The investigator must maintain the original, signed ICF. A 
copy of the signed ICF must be given to the participant and/or their legally authorized 
representative.  
For all cohorts, participants who are capable of providing informed consent at Screening may be 
requested to identify a legally authorized representative who can provide consent on their behalf 

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should they lose the capacity to consent over the course of the study. If, in the opinion of the 
investigator, the participant’s capacity to consent has been compromised at any point after 
signing the ICF, the legally authorized representative will be asked to provide consent on behalf 
of the participant. Procedures used to assess capacity to consent and identify legally authorized 
representatives must be in accordance with local practice and regulations. 
Throughout the study, participants and/or their legally authorized representatives should be 
informed of any changes made to the study and as new safety and or risk information becomes 
known. The provision of this information will be documented in the participant’s source records, 
and when applicable, an updated ICF will be provided. 
16.4. 
Data Protection 
• Participants will be assigned a unique identifier by the sponsor. Any participant 
records or datasets that are transferred to the sponsor will contain the identifier only; 
participant names or any information which would make the participant identifiable 
will not be transferred. 
• The participant must be informed that his/her personal study-related data (including 
but not limited to, retained biological samples, images and/or recordings) will be used 
by the sponsor in accordance with local data protection law. The level of disclosure 
must also be explained to the participant who will be required to give consent for 
their data to be used as described in the informed consent.  
• The participant must be informed that his/her medical records may be examined by 
Sage Quality Assurance auditors or other authorized personnel appointed by the 
sponsor, by appropriate IRB/IEC members, and by inspectors from regulatory 
authorities. 

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17. 
DATA HANDLING AND RECORDKEEPING 
17.1. 
Inspection of Records 
Sage or its representative(s) will be allowed to conduct visits at the investigation site and/or 
supporting facilities for the purpose of monitoring any aspect of the study. The investigator 
agrees to allow the monitor to inspect the facility, drug storage area, drug accountability records, 
participant medical records and study source documents, and other records relative to study 
conduct. 
Inspection of the study by a regulatory authority may occur at any time. The investigator must 
agree to the inspection of study-related records and source documents by the regulatory authority 
representative(s).  
17.2. 
Retention of Records 
The principal investigator must maintain all documentation relating to the study for the period 
outlined in the site contract, or for a period of 2 years after the last marketing application 
approval, and until there are no pending or contemplated marketing applications in an ICH 
region or at least 2 years have elapsed since the formal discontinuation of clinical development 
of IP. The retention of records must be in accordance with local regulations (see Appendix 2, 
Section 20.1). and Sage is responsible to inform the investigator/institution as to when study 
documents no longer need to be retained.  

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18. 
PUBLICATION POLICY 
All information concerning SAGE-718 is considered confidential and shall remain the sole 
property of Sage. The Investigator agrees to use this information only in conducting the study 
and shall not use it for any other purposes without written approval from Sage. No publication or 
disclosure of study results will be permitted except as specified in a separate, written, agreement 
between Sage and the investigator. 

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20. 
APPENDIX 
20.1. 
Appendix 1: Country-Specific Changes 
Country 
Section 
Number 
Original Language in 
Country-Specific Amendment 
Updated Language for Country-Specific 
Amendment 
United 
Kingdom 
(UK) 
Section 
7.4.5 
End of study will be achieved 
when the last study participant 
completes the last study visit, as 
shown in Table 5. 
End of study will be achieved when last 
study participant completes last study visit. 
Additionally, for UK participants, end of 
study will be achieved when all sample 
analyses are completed, with the exception 
of any consented exploratory analyses as 
described in Informed Consent Form and in 
adherence with local regulation. 
Australia 
Section 12.3 
The participant or participant’s 
partner will be followed to 
determine the outcome of the 
pregnancy. The outcome of all 
pregnancies (eg, spontaneous 
abortion, elective abortion, 
normal birth) must be followed 
and documented even if the 
participant was discontinued 
from the study. The Investigator 
will collect follow-up 
information on the participant or 
participant’s partner and the 
neonate, and the information will 
be forwarded to Sage or 
designee within 24 hours of 
awareness. Generally, follow-up 
will not be required for longer 
than 6 to 8 weeks beyond the 
estimated delivery date. Any 
termination of pregnancy will be 
reported, regardless of fetal 
status (presence or absence of 
anomalies) or indication for the 
procedure. 
The participant or participant’s partner will 
be followed to determine the outcome of the 
pregnancy. The outcome of all pregnancies 
(eg, spontaneous abortion, elective abortion, 
normal birth) must be followed and 
documented even if the participant was 
discontinued from the study. The 
Investigator will collect follow-up 
information on the participant or 
participant’s partner and the neonate, and 
the information will be forwarded to Sage 
or designee. For participants in Australia, 
pregnancy follow-up will be required for 
not less than 12 months. Any termination of 
pregnancy will be reported, regardless of 
fetal status (presence or absence of 
anomalies) or indication for the procedure. 
Australia 
Section 17.2 
The principal investigator must 
maintain all documentation 
relating to the study for the 
period outlined in the site 
contract, or for a period of 2 
years after the last marketing 
application approval, and until 
there are no pending or 
contemplated marketing 
applications in an ICH region or 
at least 2 years have elapsed 
since the formal discontinuation 
of clinical development of IP. 
The principal investigator must maintain all 
documentation relating to the study for the 
period outlined in the site contract, or for a 
period of 2 years after the last marketing 
application approval, and until there are no 
pending or contemplated marketing 
applications in an ICH region or at least 
2 years have elapsed since the formal 
discontinuation of clinical development of 
IP. The sponsor will maintain all data 
relating to the study for a period of 50 years 
after the completion of the study. All 
samples intended 
 will be 
destroyed at the end of the study. 
 
 

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20.2. 
Appendix 2: Study Continuation Visit for Participants Who 
Completed Day 365 But Not Day 395 Under Protocol Version 2 
Participants who have completed their Day 365 visit but NOT their Day 395 visit under Protocol 
Version 2 and wish to continue participation under Protocol Version 3 or higher will return to the 
site for the assessments in the table below and then continue on to their Month 15 visit (see 
Table 5). The participant’s visit schedule should remain relative to the date of their Day 1 visit.  
 

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Schedule of Assessments: Study Continuation Visit 
Assessments  
Study Continuation Visit 
 
Visit can occur anytime after the Day 365 visit up to 
Day 395 (±7 days) 
Informed re-consenta 
X 
Body weight 
X 
Vital signs (including orthostatics)b  
X 
Physical examinationc 
X 
Pregnancy testd 
X 
C-SSRS (Since Last Visit) 
X 
IP dispensatione 
X 
IP self-administrationf 
X 
AEs/SAEs 
X 
Prior and concomitant medications and 
procedures/therapies 
X 
Abbreviations: AE = adverse event; C-SSRS = Columbia–Suicide Severity Rating Scale; IP = investigational 
product; SAE = serious adverse event.  
a 
Both participants and study partners (if applicable) will be re-consented during at the Study Continuation visit. 
A legally authorized representative may consent on behalf of participants who are not capable of providing 
informed consent in the opinion of the investigator. 
b 
Vital signs include body temperature, respiratory rate, heart rate, and blood pressure. Vital signs will be 
measured prior to dosing. Blood pressure and heart rate will be measured after the participant has been in the 
supine position for at least 5 minutes and then repeated approximately 1 and 3 minutes after standing. Vital 
signs can be repeated once if out of range. 
c 
Physical examinations will include a brief assessment of general appearance, cardiovascular, respiratory, 
gastrointestinal, and neurological systems and followed by a targeted physical assessment as needed. A 
symptom-directed examination may be conducted at any time at the discretion of the investigator.  
d 
Urine pregnancy tests will be conducted for female participants that are not postmenopausal or surgically 
sterile. 
e 
Study staff will dispense sufficient IP for the participant to take daily at home until Month 15 visit. 
f 
Participants will self-administer IP in the clinic under the supervision of study staff. All scheduled safety 
assessments will be conducted prior to dosing. Participants should continue to self-administer IP daily at home 
following the Study Continuation Visit.