A Phase 2a Study Evaluating the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of CY6463 When Administered to Participants With Alzheimer's Disease and Vascular Pathology
Phase: PHASE2
Conditions: Alzheimer's Disease With Vascular Pathology
Sponsor: Tisento Therapeutics



CY6463 
Cyclerion Therapeutics, Inc. 
Protocol: C6463-202 Amendment 3 
16 December 2021 
 
 
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1. 
PROTOCOL SUMMARY  
1.1. 
Synopsis 
 
Name of sponsor:  Cyclerion Therapeutics, Inc.  
Name of investigational product:  CY6463 (alias IW-6463) 
Name of active ingredient:  CY6463 
Protocol number:  C6463-202  
Phase:  2a 
Country:  United States (US) 
Study title: A Phase 2a study evaluating the safety, tolerability, pharmacokinetics, and 
pharmacodynamics of CY6463 when administered to participants with Alzheimer’s disease and 
vascular pathology 
Primary objective and endpoint: 
Objective: To evaluate the safety and tolerability 
of CY6463 when administered to participants 
with Alzheimer’s disease with vascular pathology 
(ADv) 
 
Endpoint: Incidence of treatment-emergent 
adverse events (TEAEs) from study drug 
initiation through Follow-up 
Study design: 
C6463-202 is a multicenter, randomized, placebo-controlled, double-blind, sponsor unblinded study 
evaluating CY6463 vs placebo in participants with ADv.  
Participants will be randomized in a 1:1 ratio to receive either CY6463 or placebo once daily (QD) for 
approximately 87 sequential days. They will complete a total of 7 scheduled visits over the course of 
the study per the Schedule of Events, from Screening through Follow-up. 
For scheduled visits that occur on a dosing day, participants will take their study drug dose during the 
visit to allow for appropriate timing of pre- and postdose assessments. In conjunction with these 
Treatment period visits, SDUWLFLSDQWV ZLOO IDVW IRU  hours before clinical laboratory samples are 
collected. All other study drug doses will be self-administered at home. Participants will be instructed 
to take their QD dose at a consistent time (preferably ±1 hour) throughout the Treatment period. 
CY6463 may be taken with or without food. 
Randomized participants (planned):  ~30 
Study centers (planned): up to 10 
Diagnosis and main criteria for inclusion: Individuals 60 years of age and older with mild cognitive 
impairment and clinical and/or imaging findings supporting the diagnosis of Alzheimer’s disease and 
who satisfy all other eligibility criteria, with a goal of including those with subcortical, small-vessel 
disease and excluding those with large-vessel disease and/or history of large infarcts. 
Investigational product, dosage, and mode of administration:  
CY6463 tablets (5 mg) taken orally on a 15-mg QD regimen 
Reference therapy:  
Placebo-to-match CY6463 tablets taken orally on a 3-tablet QD regimen 
Duration of study drug dosing and overall study participation for each individual:  
Each participant will receive study drug (CY6463 or placebo) for approximately 12 weeks (~87 days). 
Overall individual study duration will be approximately 5 months, including the Screening, 
Treatment, and Follow-up periods.  

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Safety assessments:   
AEs, clinical safety laboratory tests, vital signs, physical examinations, 12-lead electrocardiograms 
Statistical methods: 
Sample size justification: A sample size of approximately 30 randomized participants was determined 
outside of statistical considerations and is considered sufficient to address the primary research 
objectives. 
General considerations: Corresponding with the primary objective, TEAE incidence (number and 
percentage of participants with TEAEs) will be reported for each treatment group (placebo, CY6463). 
Continuous variables will be summarized using number of participants, mean, SD, minimum, median, 
interquartile range, and maximum values. Categorical variables will be summarized using the 
frequency and percentage of participants in each category. Percentages will be based on the total 
number of participants with non-missing values. If values are missing, the number missing will also 
be presented, but without a percentage. Data summaries will be presented by treatment group. All 
available data will be included. 
 

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1.2. 
Study Schematic 
 
Figure 1: 
Study Design Schematic 
 
 
1.3. 
Schedule of Events and Assessments 
Table 1 provides the timing of the events and assessments to be conducted in this study. Also refer to the appropriate sections of this 
protocol and accompanying study manuals (eg, laboratory, pharmacy, imaging) for more information.  
Day 101 (±4) 
F/U visit
Screening visit
(Day -60 to Day -4)
SCREENING
PERIOD
60 days
TREATMENT PERIOD
87 (±4) days
FOLLOW-UP
PERIOD
14 (±4) days
Day 1
Day 87 (±4) 
/ EoT
Day 15 (±2)
Day 58 (±4)
Day 29 (±4)
Placebo QD 
--or--
=visit; EoT=end of treatment; F/U=Follow-up; QD=once daily; W=Week
15 mg CY6463 QD 

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2. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF 
FIGURES  
1. 
PROTOCOL SUMMARY ............................................................................................2 
1.1. 
Synopsis ........................................................................................................................2 
1.2. 
Study Schematic ...........................................................................................................4 
1.3. 
Schedule of Events and Assessments ...........................................................................4 
2. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES .................7 
3. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS.............................11 
4. 
INTRODUCTION ......................................................................................................13 
4.1. 
Name and Description of Study Drug ........................................................................13 
4.2. 
Description of Study Population and Rationale ..........................................................13 
4.3. 
Findings from Nonclinical and Clinical Studies .........................................................14 
4.3.1. 
Nonclinical Studies .....................................................................................................14 
4.3.2. 
Clinical Studies ...........................................................................................................14 
4.4. 
Risk/Benefit ................................................................................................................14 
4.5. 
Compliance Statement ................................................................................................14 
5. 
OBJECTIVES AND ENDPOINTS ............................................................................15 
6. 
INVESTIGATIONAL PLAN .....................................................................................15 
6.1. 
Overall Study Design ..................................................................................................15 
6.1.1. 
Screening Period .........................................................................................................16 
6.1.2. 
Treatment Period ........................................................................................................16 
6.1.3. 
Follow-up Period ........................................................................................................16 
6.1.4. 
Scientific Rationale for Study Design ........................................................................16 
6.2. 
Number of Study Centers and Participants .................................................................17 
6.3. 
Treatment Assignment, Blinding, and Data Review ..................................................17 
6.3.1. 
Randomization Procedure ...........................................................................................17 
6.3.2. 
Blinding/Unblinding and Data Review ......................................................................17 
6.3.2.1. 
Unblinding for Safety Purposes ..................................................................................17 
6.4. 
Justification for Dose Regimen ..................................................................................18 
6.5. 
Criteria for Study Termination (Study Stopping Rules) .............................................18 
6.6. 
End of Study Definition ..............................................................................................19 

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7. 
PARTICIPANT SELECTION, LIFESTYLE RESTRICTIONS, AND 
EARLY WITHDRAWAL CRITERIA .......................................................................19 
7.1. 
Inclusion Criteria ........................................................................................................19 
7.2. 
Exclusion Criteria .......................................................................................................21 
7.3. 
Trial Population Diversity ..........................................................................................23 
7.4. 
Screen Failures ............................................................................................................24 
7.5. 
Lifestyle Restrictions ..................................................................................................24 
7.5.1. 
Meals and Diet ............................................................................................................24 
7.5.2. 
Caffeine, Alcohol, and Tobacco/Nicotine ..................................................................24 
7.5.3. 
Contraception Requirements for Male Participants of Reproductive Potential ..........25 
7.5.4. 
Physical Activity .........................................................................................................25 
7.6. 
Discontinuation of Study Drug in Individual Participants .........................................25 
7.7. 
Lost to Follow-up .......................................................................................................26 
7.8. 
Replacement of Randomized Participants ..................................................................27 
8. 
STUDY DRUG AND CONCOMITANT MEDICATION 
ADMINISTRATION ..................................................................................................27 
8.1. 
Study Drug Regimen ..................................................................................................27 
8.2. 
Dose Modification in Individual Participants .............................................................28 
8.3. 
Study Drug Supply and Dosing Compliance ..............................................................28 
8.4. 
Treatment and Tracking of Overdose .........................................................................28 
8.5. 
Continued Access to Study Drug after the End of the Study .....................................29 
8.6. 
Study Drug Preparation, Handling, Storage, and Accountability ...............................29 
8.6.1. 
Accountability .............................................................................................................29 
8.6.2. 
Disposal ......................................................................................................................29 
8.7. 
Concomitant Medications and Therapies ...................................................................29 
8.7.1. 
Prohibited Medications ...............................................................................................30 
9. 
STUDY ASSESSMENTS AND PROCEDURES ......................................................30 
9.1. 
Informed Consent .......................................................................................................30 
9.2. 
MMSE.........................................................................................................................30 
9.3. 
Demography, Medical History, and Baseline Medications ........................................31 
9.4. 
Physical Examination .................................................................................................31 
9.5. 
Electrocardiograms (ECGs) ........................................................................................31 
9.6. 
Vital Signs ..................................................................................................................32 

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9.7. 
Laboratory Assessments .............................................................................................32 
9.7.1. 
Genetics ......................................................................................................................32 
9.7.2. 
Safety Laboratory Assessments ..................................................................................32 
9.7.3. 
PK and Biomarker Evaluations (Plasma and CSF) ....................................................33 
9.7.3.1. 
Plasma Sampling ........................................................................................................34 
9.7.3.2. 
CSF Sampling .............................................................................................................34 
9.8. 
Suicidal Risk Monitoring (C-SSRS) ...........................................................................34 
9.9. 
Participant Diary for Recording Daily Dosing, Concomitant Medications, 
and Changes in Health Status .....................................................................................34 
9.10. 
Adverse Events, SAEs, and Other Safety Reporting ..................................................34 
9.10.1. 
Time Period, Frequency, and Reporting Information .................................................35 
9.10.1.1. 
Follow-up of AEs, AESIs, and SAEs .........................................................................35 
9.10.1.2. 
Post-Study Events .......................................................................................................35 
9.10.2. 
Method of Detecting AEs and SAEs ..........................................................................35 
9.10.3. 
Regulatory Reporting Requirements for SAEs ...........................................................35 
9.10.4. 
Pregnancy Reporting and Monitoring ........................................................................36 
9.11. 
Cognitive Performance Assessments ..........................................................................36 
9.12. 
Neurophysiological Assessments ...............................................................................37 
9.12.1. 
Resting State qEEG (Eyes Open/Closed) ...................................................................37 
9.12.2. 
Auditory Oddball Assessment for Event-Related Potential (ERP) ............................38 
9.13. 
Neuroimaging Assessments ........................................................................................38 
10. 
STATISTICAL CONSIDERATIONS .......................................................................38 
10.1. 
Statistical Hypotheses .................................................................................................38 
10.2. 
Sample Size Determination ........................................................................................38 
10.3. 
Populations for Analyses ............................................................................................39 
10.3.1. 
Determination of PD Evaluable Population ...............................................................39 
10.4. 
Statistical Analyses .....................................................................................................39 
10.4.1. 
General Considerations ...............................................................................................39 
10.4.2. 
Primary Endpoint(s) ....................................................................................................39 
10.4.3. 
Exploratory Endpoint(s) .............................................................................................40 
10.4.4. 
Safety Analyses ..........................................................................................................40 
10.4.5. 
Other Analyses ............................................................................................................41 
10.5. 
Interim Analyses .........................................................................................................41 

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11. 
LIST OF REFERENCES ............................................................................................42 
APPENDIX 1. REGULATORY, ETHICAL, AND STUDY OVERSIGHT 
CONSIDERATIONS ..................................................................................................44 
APPENDIX 2. ADVERSE EVENTS, AESIS, AND SAES: DEFINITIONS AND 
PROCEDURES FOR RECORDING AND EVALUATING.....................................47 
APPENDIX 3. PROHIBITED MEDICATIONS, FOODS, AND SUPPLEMENTS .................50 
APPENDIX 4. NATIONAL INSTITUTE ON AGING / ALZHEIMER’S 
ASSOCIATION CRITERIA FOR AD DEMENTIA .................................................51 
APPENDIX 5. SPONSOR’S SIGNATURE PAGE ...................................................................53 
APPENDIX 6. INVESTIGATOR’S AGREEMENT..................................................................54 
 
LIST OF TABLES 
Table 1: 
Schedule of Events .......................................................................................................5 
Table 2: 
Study Drug Identification and Dosing Regimen ........................................................27 
Table 3: 
Protocol-Required Laboratory Assessments...............................................................33 
 
LIST OF FIGURES 
Figure 1: 
Study Design Schematic ...............................................................................................4 
 
  

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Abbreviation/Term 
Definition 
IW-6463 
CY6463 
IWRS 
interactive voice/web response system 
LAR 
legally authorized representative 
MedDRA 
Medical Dictionary for Regulatory Activities 
min 
minute(s) 
MMRM 
mixed-effect model repeated measures 
MMSE 
Mini-Mental State Examination 
MRI 
magnetic resonance imaging 
NO 
nitric oxide  
PD 
pharmacodynamic(s) 
PDE5 
phosphodiesterase 5 
PK 
pharmacokinetic(s) 
PT 
preferred term 
QD 
once daily 
qEEG 
quantitative electroencephalography 
QT 
the time between the beginning of the QRS (ventricular polarization) complex 
and the end of the T-wave 
QTcF 
QT interval corrected for HR using Fridericia’s formula 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
standard deviation 
sGC 
soluble guanylate cyclase 
SOC 
system organ class 
TEAE 
treatment-emergent adverse event 
ULN 
upper limit of normal 
US 
United States 

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4. 
INTRODUCTION 
4.1. 
Name and Description of Study Drug 
CY6463 (also known as IW-6463) is an orally administered central nervous system 
(CNS)-penetrant stimulator of soluble guanylate cyclase (sGC), a signaling enzyme that 
catalyzes the formation of cyclic guanosine 3’,5’-monophosphate (cGMP) from guanosine 
triphosphate in response to nitric oxide (NO) binding. Intracellular cGMP regulates vascular tone 
and regional blood flow, fibrosis, and inflammation, and has been implicated in neuronal 
survival and cognitive function. 
CY6463 is being investigated as a treatment for individuals with Alzheimer’s disease (AD). It is 
intended for administration only to eligible participants in accordance with this protocol. See 
Section 8 for additional study drug product details. 
4.2. 
Description of Study Population and Rationale 
AD is a progressive degenerative disorder that affects 40 to 50 million individuals worldwide.(1) 
A report released in 2020 estimates more than 5 million Americans ages 65 and older are living 
with AD—and that number is expected to nearly triple by the year 2050.(2) Due to its significant 
impact on memory and other mental functions, AD is emotionally and financially devastating to 
both patients and their families/caregivers, with an estimated global cost in the $1-trillion 
range.(3) Recent drug development in this therapeutic area has been focused on clearing the 
disease’s pathological hallmarks (beta amyloid plaques and tau protein-containing tangles), but 
these approaches have not yet translated into viable therapies. Currently available treatments 
show only a modest effect on symptoms and do not address the underlying disease pathology. 
Therefore, new approaches to treatment and new therapies are urgently needed. 
The role of vascular pathology in AD has recently received increased attention and, more 
specifically, the role of the NO-sGC-cGMP pathway in the pathogenesis of this disease.(4-6) 
In AD and related dementias, endothelial cell loss and NO dysregulation are major contributing 
factors to cognitive impairment and progression and result in reduced cerebral blood flow, 
vascular leakage, inflammation, and neuronal dysfunction and loss.(4, 6, 7) Because this 
pathway has been shown to have impacts on cognition, neuroprotection, neuroinflammation, and 
bioenergetics, it has the potential to serve as a target for new therapies. 
As a CNS-penetrant sGC stimulator, CY6463 has the potential to preferentially modulate the 
NO-sGC-cGMP pathway and provide therapeutic benefit for individuals with AD. This study 
will focus on individuals with AD with vascular pathology (ADv)—a subset of the larger AD 
population who have vascular pathology and cardiovascular risk factors. It is hypothesized that 
the ADv population is likely to receive more benefit and respond more favorably to CY6463 due 
to CY6463’s impact on vascular biology. 
Individuals 60 years of age and older with mild cognitive impairment and clinical and/or imaging 
findings supporting the diagnosis of AD and vascular pathology and who satisfy all other 
eligibility criteria will be enrolled. This study will aim to include participants with subcortical, 
small-vessel disease and to exclude those with large-vessel disease and/or history of large 
infarcts. 

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4.3. 
Findings from Nonclinical and Clinical Studies 
4.3.1. 
Nonclinical Studies 
Findings from nonclinical studies support the hypothesis that sGC stimulation may have 
beneficial effects across several key aspects of AD pathology and thus may serve as a viable 
treatment option for patients. Refer to the most recent CY6463/IW-6463 Investigator’s Brochure 
(IB) for more detail. 
4.3.2. 
Clinical Studies 
Safety and pharmacokinetic (PK) data from study C6463-101 in healthy adults together with 
safety, PK, and pharmacodynamic (PD) data from study C6463-102 in healthy elderly adults 
support further clinical investigation of CY6463. Information regarding these studies is available 
in the IB. 
4.4. 
Risk/Benefit  
Results from the nonclinical efficacy and safety assessment program support a favorable 
risk/benefit assessment. Clinical evaluation of CY6463 thus far has been limited to healthy 
participants; direct benefit to a patient population has not yet been determined.  
Evaluation of CY6463 in individuals with ADv is justified based on the minimal risk profile 
reported in healthy participants (including elderly) who have received CY6463, along with the 
potential benefit based on the pharmacological effects observed in nonclinical studies. Indirect 
benefits to participants include increased medical care/attention, a better understanding of their 
disease, and satisfaction knowing that their participation will contribute to AD research and 
potential therapeutics. Refer to the IB for more information. 
Procedures and assessments included in this protocol are generally consistent with standard of 
care for monitoring and/or diagnosing disease in patients with AD and with vascular pathology. 
Although magnetic resonance imaging (MRI), blood sampling, and lumbar punctures represent 
the highest burden of the study assessments for participants, these assessments present minimal 
risk and a low probability of harm. The duration and frequency of MRI procedures, blood 
sampling volumes and frequency, and the number of lumbar punctures have been minimized to 
reduce the risk to study participants and to collect only the information necessary to support 
further development of CY6463. 
Study stopping rules are discussed in Section 6.5.  
4.5. 
Compliance Statement 
See Appendix 1. 

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Participants will be randomized per Section 6.3.1 to receive approximately 87 sequential days of 
either CY6463 or placebo once daily (QD), and will complete a total of 7 scheduled visits over 
the course of the study from Screening through Follow-up. For all scheduled visits that occur on 
a dosing day, participants will take their dose during the visit to allow for appropriate timing of 
pre- and postdose assessments. All other doses will be self-administered at home. Total study 
duration for each participant will be approximately 5 months.  
6.1.1. 
Screening Period 
The Screening period begins with the execution of the informed consent form (ICF) at the 
Screening visit. After signing the ICF, each participant’s study eligibility will be assessed 
according to the study’s Inclusion Criteria and Exclusion Criteria listed in Section 7. 
After the Screening visit, participants who are eligible for enrollment must begin complying with 
the lifestyle restrictions detailed in Section 7.5. They will also begin completing their daily study 
diary (Section 9.9). 
The end of the Screening period will coincide with the start of the Treatment period. 
Collection of adverse events (AEs) will begin after the ICF is signed and will continue through 
the Follow-up period. 
6.1.2. 
Treatment Period 
The Treatment period begins on Day 1 (there is no “Day 0”) when participants undergo baseline 
procedures at the study center and receive their first QD dose of study drug. They will return to 
the study center on approximately Day 87 for the End-of-Treatment (EoT) visit; all other 
scheduled visits during this period will be completed within the timeframe allowed per Table 1. 
Throughout the Treatment period, participants will continue completing their daily study diary 
(Section 9.9). 
6.1.3. 
Follow-up Period 
The Follow-up period begins immediately after the EoT visit. During this period, participants 
will continue to comply with all lifestyle restrictions (Section 7.5) and will continue to complete 
their daily study diary.  
6.1.4. 
Scientific Rationale for Study Design 
An investigator- and participant-blinded, placebo-controlled, randomized design was selected to 
provide comparable treatment groups and to minimize selection and investigator bias in 
accordance with the concepts in ICH E10, Choice of Control Groups and Related Issues in 
Clinical Trials (International Conference on Harmonisation [ICH] of Technical Requirements for 
Registration of Pharmaceuticals for Human Use, 2001). Placebo was chosen as the control to 
determine the rate of spontaneously occurring treatment-emergent adverse events (TEAEs), and 
to reduce the potential for bias in the reporting of AEs. 
This study has a 12-week Treatment period to explore the effects of CY6463 compared with 
placebo control. The treatment duration is believed to be sufficient to evaluate the safety profile 
of CY6463 as well as observe changes in the study’s neurophysiological, PD, and cognitive 
assessments. In addition, the study includes a follow-up visit 2 weeks after the final dose of study 

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drug to monitor for any delayed-onset AEs and if any AEs that were ongoing at the EoT visit 
have resolved. Two weeks represents an interval longer than 5 half-lives of the study drug; at this 
timepoint, the remaining level of any free study drug will be negligible.  
This study is designed to select participants with mild dementia, confirmed AD pathology, 
cardiovascular risk factors, and evidence of subcortical small-vessel disease. This is a 
homogeneous population hypothesized to respond more favorably to CY6463 considering the 
compound's potential impact on vascular biology and neurophysiology. 
6.2. 
Number of Study Centers and Participants 
The study will be conducted at up to 10 study sites in the United States (US). It is expected that 
approximately 30 participants will be randomized. 
6.3. 
Treatment Assignment, Blinding, and Data Review 
6.3.1. 
Randomization Procedure 
Participants who are eligible per the criteria in Section 7 will be randomized on Day 1 to a 
double-blinded regimen of either CY6463 or placebo (1:1 ratio) via central randomization using 
an interactive voice/web response system (IWRS).  
Before the study is initiated, the directions for the system will be provided to each site. The 
computer-generated randomization schedule will be prepared by an independent statistician not 
otherwise associated with the study. 
6.3.2. 
Blinding/Unblinding and Data Review  
This will be an investigator- and participant-blinded, sponsor-unblinded study. The following 
practices will apply: 
x Sponsor review of unblinded data will facilitate decision making on project progress 
and potentially trigger plans for additional studies. 
x A Sponsor Data Review Committee (DRC), which will consist of the sponsor 
program director, medical director, senior management (medical) representative, will 
review unblinded data at the aggregate level for decision-making purposes. The DRC 
will not have access to specific participant treatment assignments so as to limit 
potential bias in discussions with the study sites. The sponsor’s biostatisticians and 
programmers will, however, have access to participants’ randomization assignments 
for analysis purposes. The remaining members of the core sponsor study team and the 
entire contract research organization (CRO) study team will be blinded. 
x The DRC charter will outline the specific individuals involved, the frequency and 
activities involved in this review, and measures taken to maintain the integrity of the 
study.  
6.3.2.1. 
Unblinding for Safety Purposes 
Except in a medical emergency, the investigator and study center staff will remain blinded 
during the conduct of the study and until, at a minimum, all discrepancies in the clinical database 

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are resolved (ie, at the time of the database lock). Unblinding of a participant’s treatment 
assignment to the investigator and study center staff is restricted to emergency situations in 
which knowledge of the treatment is necessary for the proper handling of the participant. 
Participant safety must always be the first consideration in making such a determination. If the 
investigator decides that unblinding is warranted, the investigator should make every effort to 
contact the CRO-based medical monitor prior to unblinding a study drug assignment unless this 
would delay emergency treatment of the participant. Individual treatment assignment unblinding 
is available to the investigator through the IWRS in the event of an emergency. If the treatment 
blind for the investigators (and/or study center staff) is broken, the reason and the date should be 
recorded and signed by the investigator in the source documentation and the electronic case 
report form (eCRF), and information regarding the unblinding should be submitted as soon as 
possible (within 24 hours) to the sponsor. In addition, the affected participant will be 
immediately discontinued from study drug and should follow early EoT procedures 
(Section 7.6). Unblinding of the sponsor for safety reporting will be detailed in the safety 
management plan.  
6.4. 
Justification for Dose Regimen 
CY6463 (15 mg QD) will be orally administered for approximately 87 days. A dosing duration 
of approximately 12 weeks is supported by nonclinical toxicology results in rats and dogs. The 
15-mg QD dose was selected based on safety, tolerability, and PK data (including cerebral spinal 
fluid [CSF] concentrations) from Phase 1 studies conducted in healthy adults aged 18 to 
79 years; no safety concerns were identified. Among the healthy participants who received 
CY6463, including at the highest dose levels (50 mg as a single dose, and 15 mg as a QD dose 
for 14 days in both younger adult and elderly participants), there were no discontinuations due to 
AEs and no serious adverse events (SAEs) reported. All AEs were considered mild or moderate 
by the investigator. PK data were linear and predictable, supportive of QD dosing, and were not 
impacted by food. At steady state, a 15-mg QD dose resulted in maximum concentrations that 
were above the threshold anticipated to be pharmacologically active in the CSF based on 
nonclinical studies. Refer to the most recent IB for details.  
6.5. 
Criteria for Study Termination (Study Stopping Rules) 
Participant safety will be monitored during the study by the sponsor’s medical and safety team 
who will review emerging safety data in blinded fashion, including clinical laboratory 
parameters and AEs at appropriate intervals. They will also meet on an ad hoc basis during the 
study if an unanticipated trend or signal emerges.  
The decision to terminate the study for safety reasons will be made by the sponsor. The sponsor 
will terminate the study if either of the events listed below is reported during the study: 
x SAEs in 2 participants that are considered study drug related by the sponsor and that 
code to the same Medical Dictionary for Regulatory Activities (MedDRA) system 
organ class (SOC) 
x An overall pattern of clinically significant TEAEs or change in any safety parameter 
that may appear minor in terms of an individual event but, in the opinion of the 
sponsor, collectively represent a safety concern 

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See Section 7.6 for discontinuation criteria for individual participants. 
6.6. 
End of Study Definition 
The end of the study is defined as completion of the final participant’s Follow-up visit, 
independent of whether study drug was prematurely discontinued in that individual. 
7. 
PARTICIPANT SELECTION, LIFESTYLE RESTRICTIONS, 
AND EARLY WITHDRAWAL CRITERIA 
Prospective approvals of deviations from prespecified recruitment and enrollment criteria, also 
known as a protocol waiver or exemption, are not permitted. 
Please note:  
x All Screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a Screening log 
to record details of each participant screened in order to confirm eligibility or the 
reason(s) for screening failure, as applicable (see Section 7.4). 
 Laboratory assessments may be repeated if an error is suspected. Laboratory, 
electrocardiogram (ECG), or blood pressure (BP) values that are outside the range 
specified in the protocol’s eligibility criteria may be repeated, after consultation 
with the CRO-based medical monitor. 
 After consultation with the Sponsor’s medical monitor, the investigator may 
rescreen a prospective participant should that individual discontinue during the 
Screening period due to a visit window deviation or other administrative reason. 
Participants who are rescreened will be required to sign a new ICF. 
x When investigators are to determine whether a particular finding from the Screening 
evaluations is clinically significant, they will consider whether the finding could 
prevent the individual from performing any of the protocol-specified assessments, 
represents a condition that should exclude the individual from the study, represents a 
safety concern if the individual participates in the study, or could confound the study-
specified assessments. 
7.1. 
Inclusion Criteria 
Each participant must meet each of the following criteria to be eligible for entering this study. 
1. Provides written informed consent prior to the performance of any protocol-specified 
procedure or, if unable to provide informed consent due to cognitive status, provides 
assent to participate, with a legally authorized representative (LAR) providing written 
informed consent on behalf of the participant.  
      Note:  
x If the participant requires a caregiver, a stable caregiver/study partner must also agree 
to participate as a designated caregiver in the study by agreeing, for example, to 

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accompany the participant to study visits, manage at-home study drug dosing 
compliance, and assist with diary completion. See Appendix 1. 
x Procedures conducted as part of the participant’s routine clinical management 
(eg, blood count) and obtained before signing of the ICF may be used for screening 
purposes where noted, provided that the procedures meet the protocol-specified 
criteria and were performed within the timeframe defined in the Schedule of Events 
and/or in the respective eligibility criteria. 
2. 60 years of age or older on the day of consent 
3. Meets core clinical criteria for probable AD dementia according to the 2011 National 
Institute on Aging–Alzheimer’s Associated guidelines (8); see Appendix 4. Can be based 
on medical history. 
4. Mini-Mental State Examination (MMSE) score of 20 to 26 (inclusive) 
5. Confirmation of AD pathophysiology either by a prior positive amyloid positron-
emission tomography scan or a prior CSF sample HYLGHQFH RI $ȕ/tau deposition). If AD 
pathophysiology status is unknown, an aliquot from the screening CSF sample collected 
for the baseline biomarker assessment can be used to determine AD pathophysiology. 
6. 3UHVHQFH RI 2 of the following cardiovascular risk factors: 
a. Hypertension confirmed either by: diagnosis in medical history, use of 1 ongoing 
medication to treat hypertension, or consistent (as determined by the investigator) 
history of systolic and/or diastolic BP values >130 and >80 mmHg, respectively 
b. Type 2 diabetes or prediabetes confirmed either by: diagnosis in medical history, use 
of 1 ongoing medication to treat diabetes, or consistent (as determined by the 
investigator) history of clinical laboratory values of $F  and/or fasting plasma 
JOXFRVH  mg/dL 
c. Hypercholesterolemia confirmed either by: diagnosis in medical history, ongoing use 
of  medication to treat lipid imbalance, or consistent (as determined by the 
investigator) history of clinical values of total cholesterol >200 mg/dL, low-density 
lipoprotein cholesterol >130 mg/dL, and/or triglycerides >150 mg/dL 
d. Body mass index (BMI)  NJP2 
7. MRI (existing MRI obtained 6 months before Screening visit is acceptable) findings of 
mild-to-moderate subcortical small-vessel disease as determined by white-matter lesions 
with a Fazekas (9) score of 1 (ie, punctate foci) or 2 (ie, beginning confluence of foci) 
8. If receiving concomitant or chronic medication(s), has had no change for 4 weeks 
before study drug initiation and has no plans to alter the regimen(s) during the study  
9. Agrees to adhere to lifestyle restrictions (see Section 7.5) from the time of the ICF 
signature until the end of the Follow-up visit 
10. If male, agrees to refrain from donating sperm from the Screening visit through 90 days 
after taking the final study drug dose 

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11. If male, agrees WR XVH  RI WKH IROORZLQJ HIIHFWLYH FRQWUDFHSWLRQ PHWKRGV IURP WKH
signing of WKH ,&) XQWLO  days after taking the final study drug dose: 
a. If in line with the preferred and usual lifestyle, will abstain from heterosexual 
intercourse IURP WKH VLJQLQJ WKH ,&) XQWLO  days after taking the final study drug 
dose 
—or— 
b. If heterosexually active: 
 Use a combination of 2 birth control methods (1 must be highly effective). 
Examples include condom with spermicide + intrauterine device; hormonal 
contraceptive associated with the inhibition of ovulation [eg, oral or transdermal 
patch or implant] + barrier method; surgery [bilateral tubal ligation/cauterization 
or vasectomy] + barrier method)  –or— 
 Partner is surgically sterile (bilateral oophorectomy, hysterectomy, or tubal 
sterilization [tie, clip, band, or burn]) or is postmenopausal  
12. If female, is postmenopausal/not of reproductive potential, defined as: 
a. $PHQRUUKHLF IRU  consecutive months (without an alternative medical cause) and 
follicle-stimulating hormone level >40 mIU/mL (or within the testing laboratory’s 
menopausal range) at Screening  
b. $PHQRUUKHLF IRU  FRQVHFXWLYH PRQWKV LQ WKH DEVHQFH RI PHGLFDWLRQV NQRZQ WR
induce amenorrhea) 
c. Surgically sterile (bilateral oophorectomy, hysterectomy, or tubal sterilization [tie, 
clip, band, or burn])  
13. Agrees to not receive an investigational therapy or device in any other study while 
participating in this study, through the Follow-up visit 
14. Agrees to the study procedures, including undergoing lumbar puncture for CSF samples 
7.2. 
Exclusion Criteria 
A participant who meets any of the following criteria will be excluded from entering this study. 
1. Severe visual, auditory, social, or cognitive impairment as determined by the investigator 
that may affect the ability to adhere to protocol requirements or to complete required 
assessments 
2. Diagnosis of dementia-related CNS disorder other than AD or vascular dementia 
(eg, Parkinson’s disease, Huntington’s disease, frontotemporal dementia, schizophrenia, 
Lewy body dementia) 
3. Evidence of symptomatic large-vessel disease, V\PSWRPDWLF FDURWLG DUWHU\ GLVHDVH 
occlusion) per ultrasound, large-vessel infarcts, strategic lacunar infarcts (ie, focal lesions 
found in specific sites critical for cognition and/or behavior), or infarcts >15 mm in size, 
as determined by MRI or medical history 

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4. History of significant CNS trauma (eg, cerebrovascular accident or traumatic head injury) 
or infection (eg, human immunodeficiency virus, syphilis) that has affected brain 
function, per investigator opinion 
5. Hypotension, defined as systolic BP  mmHg or diastolic BP  mmHg, at Screening 
or predose on Day 1. (Each BP recording will be the average of 3 consecutive BP 
readings conducted at intervals of 1 minute; see Section 9.6) 
6. Orthostatic hypotension at Screening or predose on Day 1. (Orthostatic hypotension is 
defined as a decrease in systolic BP of 20 mmHg, or a decrease in diastolic BP of 
10 mmHg, between 1–3 minutes after assuming a standing position vs BP while in a 
sitting or supine position.)  
7. Any contraindication to MRI procedures 
8. Any contraindication to lumbar puncture procedure, as assessed by the investigator, 
possibly including abnormalities in lumbar spine previously observed on imaging, history 
of clinically significant back pain, back pathology, spinal surgery, back injury, 
noncommunicating hydrocephalus or an intracranial mass lesion, or allergy to lidocaine 
(if planned to be used as a local anesthetic during procedure) 
9. Unable to participate in electroencephalography (EEG) protocol due to auditory 
challenges or inability to tolerate EEG cap or headphones, as determined by the 
investigator 
10. Any uncontrolled or unstable chronic disease, as determined by the investigator 
11. Clinically significant renal impairment requiring dialysis and/or history of renal 
transplant 
12. Suicidality, defined as active suicidal thoughts during the 6 months prior to Screening 
visit or at Day 1 (eg, Type 4 or 5 on the Columbia-Suicide Severity Rating Scale 
[C-SSRS]), or history of suicide attempt in previous 2 years, or at serious suicide risk, in 
investigator’s judgment 
13. Resides in a nursing home or assisted care facility with need for continuous direct 
medical care and nursing supervision. Exception: Participant may reside in such facility 
provided that continuous direct medical care is not required, a qualified caregiver is 
available for co-participation, and the participant is physically able to attend in-clinic 
study visits. 
14. Family history of short QT syndrome or long QT syndrome 
15. Clinically significant cardiac involvement or an ECG with corrected QT interval using 
Fridericia’s formula (QTcF interval) >450 ms for men or >470 ms for women.  
Note: If the first ECG QTcF interval obtained is out of range, the ECG should be 
repeated twice and the average of the 3 results should be used to determine eligibility. 
16. Any surgery or hospitalization in the 4 weeks prior to enrollment (Exception: minor 
dermatologic procedures) 
17. Recent history (eg, within prior 2 years) of 1 or more CNS bleeding event requiring 
intervention and/or hospitalization 

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Hispanics/Latinos are about one and one-half times as likely to have Alzheimer’s or other 
dementias as older Whites." While some disproportionality may be due to genetic variation, the 
greater driver is thought to be differences in socioeconomic factors and in disproportional 
comorbid health conditions associated with increased AD risk. Notably, the disproportionality of 
those comorbid conditions, including diabetes and cardiovascular disease, is also likely driven by 
socioeconomic differences.(2, 11, 12) In addition, racial and ethnic groups may also experience 
and respond to treatments differently due to the same differential factors.  
It is important for clinical trial populations to reflect the targeted patient population and/or to 
enrich for participants expected to respond differentially based on scientific rationale. 
Appropriately representative trial populations are an important facet of clinical trial designs and 
contribute to the scientifically rigorous evaluation of a drug to ensure that the safety and efficacy 
profile of a treatment is accurate.  
This study is expected to randomize approximately 30 participants with ADv in the US. To be 
eligible, participants must have evidence of AD and of vascular pathology as well as 2 of 
4 cardiovascular risk factors (hypertension, type 2 diabetes, hypercholesterolemia, and/or BMI 
 kg/m2)—criteria that are disproportionately experienced by some minority groups. Although 
recruiting a trial population representative of the US ADv population is limited by the small size 
of this study, efforts to enroll an appropriately diverse study population may include, but are not 
limited to, opening site(s) in racially/ethnically representative communities, enlisting 
investigators representative of the population, participating in outreach activities in 
representative communities, and ensuring that participant- and community-focused materials are 
culturally relevant and accessible to a broad range of backgrounds.  
7.4. 
Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently randomized to study drug. The investigator will maintain a screening log to 
record details of all prospective participants screened and to confirm eligibility or record reasons 
for screening failure, as applicable. A minimal set of screen failure information is required to 
ensure transparent reporting of participants who screen fail, to respond to queries from regulatory 
authorities, and to meet the Consolidated Standards of Reporting Trials publishing requirements. 
Minimal information includes demography, reason(s) for screen failure, eligibility criteria met 
and/or not met, and AE details. 
7.5. 
Lifestyle Restrictions 
Participants will be instructed to follow the lifestyle restrictions below. 
7.5.1. 
Meals and Diet 
Participants will fast (water is allowed) for at least 4 hours before clinical laboratory assessments 
at all scheduled visits except the Screening visit. 
7.5.2. 
Caffeine, Alcohol, and Tobacco/Nicotine 
Caffeine: Participants should not consume excessive amounts of caffeine, defined as >800 mg 
per day, from 7 days before the first dose of the study drug through the Follow-up visit. 

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Participants should abstain from any caffeine-containing products for 24 hours before each 
scheduled visit. Caffeine quantities are defined below. 
Item (serving) 
Caffeine content 
Coffee (8 oz/237 mL)  
80–100 mg 
Energy drink (8 oz/237 mL) 
40–250 mg 
Tea, green or black (8 oz/237 mL) 
30–50 mg 
Cola (12 oz/355 mL) 
30–40 mg 
Dark chocolate (1 oz/28 g) or milk chocolate (2 oz/57 g) 
12 mg 
Source: US Department of Agriculture, Agricultural Research Service. Food Data Central. 2019 [fdc.nal.udsa.gov] 
  
Alcohol: Participants should not consume alcohol within 24 hours of each scheduled visit. At 
other times throughout the study, participants should not consume >2 units of alcohol daily on 
average (1 unit=14 g pure alcohol [eg, 12 oz regular beer; 5 oz table wine; or 1.5 oz distilled 
spirits]). 
Tobacco/Nicotine: Participants should abstain from the use of tobacco- or nicotine-containing 
products (including e-cigarettes and patches) until completion of the Follow-up visit. 
7.5.3. 
Contraception Requirements for Male Participants of Reproductive Potential 
Male participants of reproductive potential must use effective contraception as defined in 
Inclusion Criteria 10 and 11 (Section 7.1), as applicable.  
Details regarding pregnancy testing and reporting, including in female partners of male 
participants, are provided in Section 9.10.4. 
7.5.4. 
Physical Activity 
Participants will abstain from strenuous exercise for 48 hours before each blood collection for 
clinical laboratory tests. Participants may participate in light recreational activities during the 
study but should maintain the same level of physical activity from Screening through the final 
Follow-up visit. 
7.6. 
Discontinuation of Study Drug in Individual Participants  
Participants will be informed that they may withdraw from the study (ie, withdraw their consent) 
at any time without prejudice to their care. Attempts should be made to determine the reason for 
the withdrawal, if possible. 
x The participant (or the LAR, if applicable; see Eligibility Inclusion 1) may request 
destruction of any samples collected but not yet tested; the investigator must 
document this request in the study records.  
x If consent is withdrawn, the sponsor may retain and continue to use any data collected 
prior to the withdrawal of consent. 

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A participant may be discontinued from study drug by the investigator or sponsor due to any of 
the following:  
x In the investigator’s opinion it is not in the best interest of that individual to continue 
x An AE (see Section 8.2 for dose modification in individuals) such as: 
 A symptomatic hypotension-related AE (eg, syncope) that requires intervention 
and is considered related to study drug 
 An ECG change from baseline that is considered to be clinically meaningful by 
the investigator (eg, abnormal Q waves, prolonged QT) 
Whenever possible, participants who prematurely discontinue from study drug but have not 
withdrawn consent should complete the EoT (except for study drug dosing) and Follow-up visits 
and associated assessments (see Table 1).  
Participants who discontinue due to an AE will be followed until resolution of all of their AEs or 
until the unresolved AEs are judged by the Investigator to have stabilized. 
A participant may be discontinued from study participation by the investigator or sponsor at 
any time for any reason, such as the participant being lost to follow-up (see Section 7.7). 
A premature discontinuation from the study will occur when a randomized individual ceases 
study participation prior to completing all study visits. The sponsor will be notified of any 
premature study discontinuation. The date the participant is withdrawn from the study and the 
reason for discontinuation will be recorded on the study termination form of the eCRF. 
Unless consent is withdrawn, the sponsor and/or sponsor’s designee may contact a participant 
after the individual’s completion or discontinuation from the study to inquire about health status 
and/or experiences in the study. 
7.7. 
Lost to Follow-up 
The following actions will be taken if a participant fails to return to the clinic for a required study 
visit: 
x The site must attempt to contact the participant and reschedule the missed visit as 
soon as possible and counsel the participant on the importance of maintaining the 
assigned visit schedule. 
x Before a participant is deemed lost to follow-up, study center personnel must make 
every effort to regain contact with the participant (ie, where possible, 3 telephone 
calls and, if necessary, a certified letter sent to the participant’s last known mailing 
address or local equivalent methods). These contact attempts will be documented in 
the participant’s source document. 
x If the participant continues to be unreachable, study center personnel or designee will 
attempt to determine the vital status of the participant within legal and ethical 
boundaries for all randomized participants, including those who did not receive study 
drug. Public sources may be searched for vital status information. If vital status is 
determined to be “deceased,” this will be documented and the participant will not be 

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considered lost to follow-up. Sponsor personnel will not be involved in any attempts 
to collect vital status. 
Should the participant continue to be unreachable and the vital status is unknown, or the 
participant is determined to be living, he/she will be considered lost to follow-up from the study.  
7.8. 
Replacement of Randomized Participants 
If participants prematurely discontinue or are considered lost to follow-up, additional participants 
may be recruited and enrolled at the discretion of the sponsor. 
8. 
STUDY DRUG AND CONCOMITANT MEDICATION 
ADMINISTRATION 
8.1. 
Study Drug Regimen 
All eligible participants will be randomized to either CY6463 (15 mg QD) or matching placebo 
QD; see Table 2. Study drug may be taken with or without food. Participants will be instructed to 
take their daily study drug dose each morning at a consistent time (preferably ±1 hour) 
throughout the Treatment period. Participants are to record the date and time of each at-home 
dose administration in their study diary (see Section 9.9). 
Exception/Note: For all scheduled visits that occur on a dosing day, participants will take 
their dose during the visit to allow for appropriate timing of pre- and post-dose assessments. 
Attempts should be made to schedule these visits such that dosing can occur at the 
participant’s approximate daily dosing time. In conjunction with these visits, participants will 
IDVW IRU  hours before clinical laboratory samples are collected. 
Table 2: 
Study Drug Identification and Dosing Regimen 
 
Study Drug 
Product name 
CY6463 
Placebo to match the CY6463 tablet 
Dosage form & 
description 
round, white to off-white solid tablet 
round, white to off-white solid tablet 
Unit dose strength 
5-mg tablet 
N/A 
Regimen* 
15 mg (3×5-mg tablet) taken QD  
3×PTM tablets taken QD  
Route of administration 
oral 
oral 
Sourcing 
Provided centrally to the study center pharmacy by the sponsor/designee 
Packaging & labeling 
Supplied in white, induction-sealed 60-cc high-density polyethylene bottles that are 
fitted with a polypropylene child-resistant cap. Each bottle contains a count of 
35 tablets and a 3-g silica gel desiccant pack and is labeled as required per country 
requirement. 
N/A=not applicable; PTM=placebo to match; QD=once daily; study drug=CY6463 or matching placebo 
* Regimen to be assigned centrally, via randomization. 
Study drug supply and dosing compliance assessment details are provided in Section 8.3. 

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8.2. 
Dose Modification in Individual Participants 
For a participant who does not tolerate the 15-mg QD dose (ie, three 5-mg tablets) as evidenced 
by an associated AE, the participant’s dose may be de-escalated to 10-mg QD dose (ie, two 5-mg 
tablets).  
x The decision to de-escalate study drug will be made on a per-participant basis jointly 
by the investigator and the CRO-based medical monitor, in consultation with the 
sponsor's medical monitor as needed; the modification will be recorded in the source 
documents and eCRF.  
x Initiation of the 10-mg QD dose should occur only after the AE(s) prompting the dose 
reduction has/have either resolved or improved sufficiently to be considered mild in 
severity or, if the AE is a worsening of a pre-existing condition, has returned to 
baseline status. 
If the 10-mg QD dose is also not tolerated, the participant will be discontinued from study drug 
for the remainder of the Treatment period due to the AE. See Section 7.6 for additional study 
drug discontinuation criteria and procedures. 
8.3. 
Study Drug Supply and Dosing Compliance 
The appropriate amount of study drug will be dispensed to randomized participants on Day 1. 
Drug will be resupplied as needed. 
When participants are dosed at the study center, they will receive study drug under medical 
supervision, directly from the investigator or designee who will examine the participant’s mouth 
to ensure that study drug was ingested. The study drug dose and the participant's identification 
will be confirmed at the time of dosing by a member of the study site staff other than the person 
administering the study drug. The date and time of each dose administered in the clinic will be 
recorded in the source documents. 
Participants and/or their caregivers/study partners, as applicable, will be asked to record the date 
and time of each at-home study drug administration in their daily study diary (Section 9.9). They 
will be asked to bring their diary to each scheduled visit. The diaries will be checked for dosing 
compliance; as applicable, participants will be reminded of the need for daily compliance with 
dosing.  
During the Treatment period, participants will also be asked to bring their study drug supply in 
the original bottles to each scheduled visit. Study drug dosing compliance will be based on tablet 
counts conducted during the Treatment period and will be documented in the source documents 
and relevant eCRF. Deviation(s) from the assigned regimen will be recorded, including dates for 
dosing delays and/or dose reductions.  
8.4. 
Treatment and Tracking of Overdose 
For this study, any reported daily dose of study drug >15 mg QD will be considered an overdose 
whether or not associated with an AE(s).  

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In the event of an overdose, the investigator/treating physician should: 
x Immediately contact the CRO-based medical monitor  
x In consultation with the CRO-based medical monitor, evaluate the participant to 
determine whether study drug should be interrupted, whether the subsequent dose 
should be reduced, and/or if plasma PK sample should be obtained 
x Closely monitor the participant for any AE(s) 
x Document the quantity of the excess dose as well as the duration of the overdose 
8.5. 
Continued Access to Study Drug after the End of the Study 
Continued access to study drug after cessation of an individual’s study participation is not 
planned. 
8.6. 
Study Drug Preparation, Handling, Storage, and Accountability 
Study drug must be stored in a secure, monitored (manual or automated) area in accordance with 
the labeled storage conditions and with access limited to the investigator and authorized study 
center staff. 
Study drug should be kept at room temperature (ie, 50°–86°F) at all times. Participants will be 
advised to report any excursion outside of this temperature range to study center staff. Study 
drug bottles must be kept tightly closed. 
8.6.1. 
Accountability 
The investigator/designee must confirm that appropriate temperature conditions have been 
maintained during transit for all study drug received and that any discrepancies are reported and 
resolved before use of the study drug. 
Only participants who are eligible per this protocol for study drug administration may receive 
study drug. Only authorized study center staff may supply study drug to the participants. 
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study drug accountability, reconciliation, and record maintenance (ie, receipt, 
reconciliation, and final disposition records). A copy of the final drug accountability log will be 
provided to the sponsor or designee. 
8.6.2. 
Disposal 
Refer to the study's pharmacy manual for study drug disposal instructions. No study drug is to be 
destroyed without prior written permission of the sponsor. 
8.7. 
Concomitant Medications and Therapies 
Any medication or vaccine (including over-the-counter or prescription medicines, recreational 
drugs, vitamins, and/or herbal supplements, or other specific categories of interest) that the 

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participant is receiving at the time of enrollment or receives during the study must be recorded 
along with: 
x Reason for use 
x Dates of administration including start and end dates 
x Dosage information including dose and frequency 
Note: Prior therapies, medications, vaccinations, surgeries, etc. (ie, before initiation of study 
drug) must be differentiated from concomitant therapies (ie, those after initiation of study drug) 
to facilitate understanding of any AEs that occur after the start of study drug.  
See Section 8.7.1 for information on medications that are prohibited in this study. In addition, 
participants will not initiate the use of additional medication (including nonprescription “over-
the-counter” preparations) for treatment of AD during the study other than the study drug.  
The CRO-based medical monitor should be contacted if there are any questions regarding 
concomitant or prior therapy. 
8.7.1. 
Prohibited Medications 
Comprehensive drug-drug interaction studies with CY6463 have not been conducted in humans. 
See Appendix 3 for a complete list of medications that are prohibited. Participants and/or their 
caregivers/study partners should be reminded of the restrictions on food, beverages, supplements, 
and other substances as noted in Section 7.5. 
The decision and need to switch medications and/or dose-reduce concomitant medications prior 
to or during study drug exposure will be made by the investigator in consultation with the study 
center pharmacist (if available) or the CRO-based medical monitor to assess the risk/benefit of 
administering the concomitant medication. 
9. 
STUDY ASSESSMENTS AND PROCEDURES 
Study assessments will be conducted according to the timing and sequence indicated in the 
Schedule of Events. Details regarding those procedures are provided below and in the study 
manuals (eg, laboratory, pharmacy, imaging).  
During any unscheduled visit, safety assessments will be conducted per investigator discretion; 
results will be documented in the source document and the appropriate eCRF. 
9.1. 
Informed Consent 
Before a potential study participant undergoes any study-specific evaluations or procedures, the 
participant (and/or participant's LAR/guardian, if applicable) must provide written, informed 
consent. See Appendix 1 for more information. 
9.2. 
MMSE 
The Mini-Mental State Examination (MMSE) consists of 11 questions that together test 5 areas 
of cognitive function: orientation, registration, attention, and calculation, recall, and language. 

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The maximum score is 30. A score of 23 or lower is indicative of cognitive impairment, and 
17 or lower indicates severe impairment. 
9.3. 
Demography, Medical History, and Baseline Medications  
At the Screening visit, demographic characteristics (eg, age, sex, race/ethnicity, apolipoprotein 
E4 [ApoE4] status if known, and highest level of education completed) will be recorded along 
with a complete medical history that will include the participant’s diagnosis of AD, evidence of 
vascular pathology, smoking history, prior and current medications (see Section 8.7), surgeries, 
and any additional relevant medical history. 
9.4. 
Physical Examination 
At Screening, a complete physical examination will be performed by the investigator and 
documented on the appropriate eCRF. All other examinations may be symptom directed at the 
investigator’s discretion.  
A complete physical examination should include examination and assessment of the following: 
General appearance 
Lymph nodes 
Nervous system  
Cardiovascular system 
Head, eyes, ears, nose, and throat 
Skin  
Respiratory system 
Neck 
Mental status  
Abdomen/liver/spleen 
Musculoskeletal system 
 
Breast, genitourinary, and rectal examinations are optional and may be performed at the 
discretion of the investigator. 
Height (cm) will be measured only at Screening. Weight (kg) will be recorded throughout the 
study per Table 1. BMI will be calculated and recorded at Screening. 
9.5. 
Electrocardiograms (ECGs) 
All ECGs will be obtained using an ECG machine that automatically calculates the heart rate and 
measures PR, QRS, QT, and QTc intervals. The ECG should be obtained after the participant has 
UHVWHG VXSLQH IRU  PLQXWHV  
If a QTc result (corrected using Fridericia’s formula) is outside of the normal range (>450 ms), 
the ECG should be repeated twice and the average of the 3 results calculated.  
All ECGs will be evaluated by an investigator or qualified designee for the presence of 
abnormalities. Results will be reported as “normal,” “abnormal clinically significant,” or 
“abnormal not clinically significant.” Abnormalities of clinical significance will be recorded as 
an AE.  
If a confirmed clinically significant abnormal result is obtained, the study center should follow 
standard institutional procedure until the result resolves to baseline. If concerns remain, escalate 
the issue to the sponsor’s medical monitor. 

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9.6. 
Vital Signs 
Vital signs will be measured before blood collection(s) and will include oral temperature (°C), 
respiratory rate, peripheral oxygen saturation, and seated-to-standing BP and pulse rate. All 
measures VKRXOG EH SUHFHGHG E\  minutes of rest for the participant in a quiet setting without 
distractions (eg, television, cell phones).  
Oxygen saturation measurements should be taken by pulse oximeter on room air. 
BP and pulse will be measured using a completely automated device. The same device 
make/model should be used for an individual participant throughout the study, if possible. 
Manual techniques will be used only if an automated device is not available.  
x Supine/semi-recumbent BP measurements: 3 consecutive BP readings will be 
recorded in the source documents at intervals of approximately 1 minute. The average 
of the 3 BP readings will be recorded in the eCRF. 
x Orthostatic BP and pulse measurements: After the supine/semi-recumbent 
measurements are collected, the participant will assume a sitting position for 1 to 
3 minutes, and finally assume a standing position for 2 (±1) minutes before the 
standing BP and pulse values are measured (single measure); these values will be 
recorded in the source document.  
x The supine/semi-recumbent average and the standing values will be used to calculate 
and record orthostatic BP and pulse in the eCRF. 
9.7. 
Laboratory Assessments 
9.7.1. 
Genetics  
Participants who do not have ApoE4 genetic status recorded in their medical records will be 
tested for ApoE4 status and for ABCA7 (adenosine 5-triphosphate [ATP]-binding cassette sub-
family A, member 7) status (if not already in their medical record), and potentially for additional 
genetic polymorphisms associated with endothelial dysfunction at Screening. Collection 
instructions are provided in the study’s laboratory manual. 
9.7.2. 
Safety Laboratory Assessments 
Tests detailed in Table 3 will be performed per Table 1 and sent to the central laboratory for 
analysis. See the study’s laboratory manual for collection and processing details.  
Except at Screening, participants will fast for 4 hours prior to safety laboratory sample 
collections.  
On Day 1 prior to randomization, clinical safety laboratory results (clinical chemistry, 
coagulation, and hematology) from the Day 1 predose sample (see Table 1 footnote b) must be 
reviewed for clinical significance to confirm eligibility and suitability for this study; local 
laboratory values may be used for this purpose provided that a separate set of the Day 1 samples 
is sent to the Central laboratory for processing and for recording in the eCRF. Laboratory 
parameter requirements for study eligibility are detailed in Section 7.1 and Section 7.2.  

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Throughout the study, the investigator is responsible for reviewing each laboratory report and for 
determining the clinical significance of any results that fall outside of the laboratory normal 
ranges; this review must be documented and filed with the source documents. Additional tests 
may be performed at any time during the study per investigator discretion or as required by local 
regulations. Laboratory assessments may also be repeated if an error is suspected.  
An abnormal laboratory value not already part of a diagnosis and that requires a change in the 
study drug or is considered clinically significant by the investigator is to be recorded as an AE. 
All laboratory values considered abnormal and clinically significant during study participation, 
including the Follow-up visit, should be repeated until the values return to normal or baseline or 
are no longer considered clinically significant by the investigator or the CRO-based medical 
monitor.  
Table 3: 
Protocol-Required Laboratory Assessments 
Assessment 
Parameter 
Hematology 
Hematocrit 
RBC indices: 
WBC count w/differential: 
 
Hemoglobin 
--Mean corpuscular hemoglobin (MCH) 
--Basophils 
--Monocytes 
 
Platelet count 
--Mean corpuscular volume (MCV) 
--Eosinophils 
--Neutrophils 
 
RBC count 
--5HWLFXORF\WHV 
--Lymphocytes 
Clinical 
chemistry 
(serum) 
Albumin 
BUN 
GGT 
Alkaline phosphatase 
Calcium 
Glucose (fasting) 
ALT/SGPT 
Creatinine 
Potassium 
AST/SGOT 
Creatine kinase 
Protein (total) 
Bilirubin (total, direct) 
Cystatin C 
Sodium 
Coagulation 
aPTT 
INR 
Prothrombin time 
Lipids 
Total cholesterol 
HDL-c 
LDL-c 
Triglycerides 
Note:  Events of ALT 3×upper limit of normal (ULN) and bilirubin î8/1 ! GLUHFW ELOLUXELQ RU $/7 3×ULN and 
INR>1.5, which may indicate severe liver injury (possible Hy’s Law), will be reported as an SAE. 
ALT=alanine aminotransferase; aPTT=activated partial thromboplastin time; AST=aspartate aminotransferase; BUN=blood urea 
nitrogen; GGT=gamma glutamyl transferase; HDL-c=high-density lipoprotein cholesterol; INR=international normalized ratio; 
LDL-c=low-density lipoprotein cholesterol; RBC=red blood cell; SGOT=serum glutamic-oxaloacetic transaminase; 
SGPT=serum glutamic-pyruvic transaminase; WBC=white blood cell 
9.7.3. 
PK and Biomarker Evaluations (Plasma and CSF) 
Samples will be collected per the Schedule of Events and the study laboratory manual. The 
actual date and time (24-h clock time) of each sample collection will be recorded in the source 
documents and eCRF. Specific instructions for the collection and handling of biological samples 
are provided in the study's laboratory manual.  
Samples collected for biomarker analysis will be used to further understand the ADv disease 
process, pathways associated with the disease state, and/or the mechanism of action of CY6463 
and its PD effect. 
 

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9.7.3.1. 
Plasma Sampling 
Sparse whole-blood samples will be collected for measurement of plasma concentrations of 
CY6463 using a validated liquid chromatography-tandem mass spectrometry bioanalytical 
method. Blood samples will also be collected to evaluate changes in concentrations of select 
disease and PD biomarkers. 
9.7.3.2. 
CSF Sampling  
CSF samples will be collected for measurement of CY6463 concentrations and for changes in the 
concentrations of select disease and PD biomarkers.  
9.8. 
Suicidal Risk Monitoring (C-SSRS) 
CY6463 is considered to be a CNS-active investigational drug. Although CY6463 and other 
similar drugs in this class have not been associated with an increased risk of suicidal thinking or 
behavior, the sponsor considers it important to monitor for such ideation or behavior before and 
during this clinical study. Therefore, participants should be appropriately monitored and closely 
observed for suicidal ideation and behavior or any other unusual change in behavior. The 
C-SSRS (13) will be administered per the Schedule of Events by an individual with appropriate 
clinical training who has taken the specific rater training for the scale, which will be provided by 
an agent of the sponsor prior to study start. If at any post-Screening visit there are “YES” 
answers on Items 4, 5 or on any behavioral question of the C-SSRS, an immediate risk 
assessment should be conducted with the CRO-based medical monitor to determine whether it is 
safe for the participant to continue in the study.  
9.9. 
Participant Diary for Recording Daily Dosing, 
Concomitant Medications, and Changes in Health Status 
At the Screening visit, each participant will be issued a study diary in which they (or their 
LAR/guardian or caregiver/study partner, as applicable) will be asked to record on a daily basis 
the name of any new and/or changes in concomitant medication(s) they take, along with the date, 
time, and dose strength of that medication(s), and any changes in health status that they 
experience (including the dates, times, and brief descriptions). They will be asked to continue 
entering this information each day throughout the study until the Follow-up visit. The diaries are 
intended to serve as reminders to the participant and caregiver/study partner and will constitute 
official source documents. During the Treatment period, participants will be instructed to also 
record the date and time of each study drug dose taken at home. 
Participants will be asked to bring their diary to each scheduled visit. Study staff will monitor the 
diaries during the visit, record any relevant data in the eCRF, and will retain the diaries as part of 
the participants' source files. A new diary will be issued at each visit, with the final diary 
collected at the Follow-up visit. 
9.10. 
Adverse Events, SAEs, and Other Safety Reporting 
The definitions of AEs, adverse events of special interest (AESIs), and SAEs can be found in 
Appendix 2. 

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Immediate safety concerns should be discussed with the study’s designated CRO-based medical 
monitor upon occurrence or awareness. Changes in the participant’s health status since the 
previous visit or previous study drug administration must be checked, including laboratory 
results, as applicable.  
9.10.1. 
Time Period, Frequency, and Reporting Information  
AEs, AESIs, and SAEs will be recorded on the AE eCRF starting from the signing of the ICF 
until the Follow-up visit after the final study drug dose.  
x SAEs will be reported within 24 hours of the investigator’s first awareness of the 
event  
x Nonserious AESIs will be reported within 5 business days of the investigator’s first 
awareness of the event 
9.10.1.1. Follow-up of AEs, AESIs, and SAEs 
After the initial AE/SAE report, the investigator is required to proactively follow each participant 
at subsequent visits/contacts. All SAEs and AESIs will be followed until resolution, stabilization, 
the event is otherwise explained, or the participant is lost to follow-up (see Section 7.7). The 
investigator will submit any updated SAE information within 24 hours of it becoming available, 
using the AE eCRF. 
9.10.1.2. Post-Study Events 
Investigators are not obligated to actively seek information on AEs or SAEs after conclusion of 
an individual’s study participation. However, if the investigator learns of any SAE, including a 
death, at any time after a participant has been discharged from the study, and considers the event 
to be reasonably related to the study drug or study participation, he/she must promptly notify the 
sponsor. 
9.10.2. 
Method of Detecting AEs and SAEs 
AEs will be reported by the participant (or, when appropriate, by the participant’s LAR, 
caregiver, study partner) spontaneously and/or in response to open-ended questioning from the 
study personnel or revealed by observation. Open-ended and nonleading verbal questioning of 
the participant will be the preferred method to inquire about AE occurrences. Care will be taken 
not to introduce bias when detecting events. 
See Appendix 2 for details regarding the recording, evaluation, and causality assessment of AEs, 
AESIs, and SAEs. 
9.10.3. 
Regulatory Reporting Requirements for SAEs 
Prompt notification by the investigator to the sponsor of an SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of a study 
drug under clinical investigation are met. 
The sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study drug under clinical investigation. The sponsor 

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will comply with country-specific regulatory requirements relating to safety reporting to the 
regulatory authority and the investigators. The principal investigator at each site will be 
responsible for notifying the relevant institutional review board (IRB)/independent ethics 
committee (IEC) of these additional SAEs, according to local standard operating procedures. 
Investigator safety reports must be prepared for suspected unexpected serious adverse reactions 
according to local regulatory requirements and sponsor policy and forwarded to investigators, as 
necessary. 
An investigator who receives an investigator safety report describing an SAE or other specific 
safety information (eg, summary or listing of SAEs) from the sponsor will review and then file it 
along with the IB and will notify the IRB/IEC, if appropriate according to local requirements. 
9.10.4. 
Pregnancy Reporting and Monitoring 
Study drug will be immediately discontinued in a female participant upon confirmation of a 
positive pregnancy test result and will be reported to the sponsor within 24 hours of first 
awareness. Pregnancy in a female partner of male participant will be reported to the sponsor 
within 24 hours after obtaining the necessary signed ICF from the female partner. The 
participant/consenting pregnant female partner will be followed to determine the outcome of the 
pregnancy. 
While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication or 
elective termination of a pregnancy for medical reasons will be reported as an AE or SAE. 
Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered SAEs and will be reported as such. Elective 
abortions without complications should not be handled as AEs.  
Any post-study pregnancy-related SAE considered reasonably related to the study drug by the 
investigator will be reported to the sponsor. While the investigator is not obligated to actively 
seek this information in former study participants or their pregnant female partners, he or she 
may learn of an SAE through spontaneous reporting. 
9.11. 
Cognitive Performance Assessments 
The following Cogstate AD battery of cognitive function tests will be completed digitally. 
x Detection test (3 min; measures processing speed): A playing card is presented face 
down. The participant is asked to press “yes” as soon as the card flips over. 
x Identification test (3 min; measures attention): A playing card is presented face 
down. When the card flips over, the participant must decide whether or not it is red. If 
the card is red, they press “yes” and if it is not, they press “no.” The participant works 
as quickly and accurately as possible. 
x One-card learning test (6 min; measures visual memory): A playing card is 
presented face up. The participant must decide whether they have seen the card before 
in the test. Accordingly, they will press “yes” or “no” as quickly and accurately as 
possible. 

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x One back test (4 min; measures working memory): A playing card is presented face 
up. The participant must decide whether the card is the same as the previous card. If 
the card is the same, the participant should press “yes” and if it is not, the participant 
should press “no.” The participant is encouraged to work as quickly and as accurately 
as possible. 
x International shopping list test (5 min; measures verbal learning): After being read 
a shopping list, the participant is asked to recall as many items from the list as 
possible.  
x International shopping list test—delayed recall (5 min; measures verbal memory): 
After some time has passed, the participant is asked to recall again as many items 
from the shopping list as possible. 
x Continuous paired associate learning test (7 min; measures visual memory): 
The participant must learn and remember the pictures hidden beneath different 
locations on the screen. 
x Modified Groton maze learning test (7 min; measures executive function): 
A 10×10 grid of tiles is presented on the screen. A 28-step pathway is hidden among 
the tiles. A blue tile indicates the start. A tile with red circles indicates the finish. The 
participant must move 1 step at a time from the start toward the finish by touching a 
tile next to their current location. If the correct move is made, a green checkmark 
appears. If the move is incorrect, a red cross appears. Once completed, the participant 
is returned to the start location to repeat the test by remembering the pathway that 
was just completed. 
The following assessments of semantic and phonemic fluency will also be completed. 
x Letter fluency (3 min; measures verbal fluency): Using the 3-letter set of F, A, and S, 
the participant is given 1 minute to name as many words as possible beginning with 
each one of the letters in turn, for a total of 3 minutes. The score is the total number 
of unique correct words. 
x Category fluency (1 min; measures verbal fluency): Using a single category of 
animals, the participant is given 1 minute to name as many unique words as possible 
within that category. The score is the total number of unique correct words. 
9.12. 
Neurophysiological Assessments  
Details of EEG procedures will be described outside of this study protocol. Because the postdose 
EEG assessment will be approximately 2 hours after the predose EEG assessment, the electrodes 
should remain in place to reduce variability and ensure consistent testing conditions. 
9.12.1. 
Resting State qEEG (Eyes Open/Closed) 
Resting state quantitative electroencephalography (qEEG) recordings will be performed with 
alternating periods of eyes open and eyes closed. During part of the recording session, 
participants will face a featureless wall and will be instructed not to stare, not to move their head 
and eyes, and to suppress eye blinks. 

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9.12.2. 
Auditory Oddball Assessment for Event-Related Potential (ERP) 
Participants will be seated wearing the EEG cap and headphones and instructed to sit still and 
relax. During this task, participants will be presented with a series of auditory tones. Of these 
tones, the majority are presented as frequent stimuli while some are presented as 
deviant/infrequent stimuli. Participants will be instructed to pay attention to the tones and 
identify the infrequent/deviant tones.  
9.13. 
Neuroimaging Assessments 
Exploratory neuroimaging modalities will be used to measure the potential PD effects of 
CY6463 in the brain. Modalities include arterial spin labeling (ASL) and functional magnetic 
resonance imaging (fMRI).  
Regional and overall changes in cerebral blood flow will be measured using ASL during resting 
state. Brain activity/reactivity will be measured using fMRI, a relative measure based on the 
blood-oxygen-dependent effect performed during resting state. MRI will also be used to detect 
subtle changes in brain tissue by quantitatively measuring changes in cellular microstructure and 
white matter structural integrity.  
Details of imaging acquisition procedures will be described outside of this study protocol. 
10. 
STATISTICAL CONSIDERATIONS 
See Section 5 for a list of the study objectives and their corresponding endpoints.  
10.1. 
Statistical Hypotheses 
The primary objective of the study is to evaluate the safety and tolerability of CY6463 (15 mg 
QD) after 12 weeks of treatment. No formal statistical hypotheses will be conducted to assess 
this objective.  
If appropriate, comparisons between CY6463 and placebo will be made to investigate the 
exploratory objectives. Such tests will be 2-VLGHG ZLWK D  VLJQLILFDQFH OHYHO Due to the 
exploratory nature of this study, there will be no adjustment of the p-values for multiple testing. 
All reported p-values will be considered nominal.  
10.2. 
Sample Size Determination 
A sample size of approximately 30 randomized participants was determined outside of statistical 
considerations and is considered sufficient to address the primary research objectives. 

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10.3. 
Populations for Analyses 
The following analysis populations are defined for this study. 
Population 
Description 
Screened  
All participants who signed the ICF 
ITT 
All randomized participants 
Safety 
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PK  
All randomized SDUWLFLSDQWV ZLWK  HYDOXDEOH SRVWGRVH 3. assessment 
PD evaluable 
$OO UDQGRPL]HG SDUWLFLSDQWV ZKR FRPSOHWHG WKH EDVHOLQH DQG (R7 YLVLW DVVHVVPHQWV KDG 
compliance with study drug dosing, and did not have any major protocol deviations that could 
affect the PD assessments  
EoT=end of treatment; ICF=informed consent form; ITT=intent-to-treat; PD=pharmacodynamic(s); PK=pharmacokinetic(s) 
10.3.1. 
Determination of PD Evaluable Population  
The PD evaluable population will be identified and documented based on a review of protocol 
deviations before database lock by members of the study team, including but not limited to the 
medical monitor and study biostatistician. The categories of major protocol deviations to be 
reviewed include, but are not limited to, participants who: 
x Did not meet key inclusion/exclusion criteria  
x Received disallowed concomitant medication that could meaningfully impact results  
x +DG WUHDWPHQW FRPSOLDQFH UDWH   
The number and percentage of participants excluded from the PD evaluable population will be 
summarized by type of deviation and by treatment arm.  
10.4. 
Statistical Analyses 
This section summarizes the planned statistical analyses of the endpoints listed in Section 5. 
A more detailed and technical description of theses analyses will be included in the statistical 
analysis plan (SAP). 
10.4.1. 
General Considerations 
Continuous variables will be summarized using the number of participants, mean, SD, minimum, 
median, interquartile range, and maximum values. Categorical variables will be summarized 
using the frequency and percentage of participants in each category. Percentages will be based 
on the total number of participants with non-missing values. If there are missing values, the 
number missing will also be presented, but without a percentage. Data summaries will be 
presented by treatment group (placebo, CY6463). All available data will be included. 
10.4.2. 
Primary Endpoint(s) 
Corresponding with the primary objective of evaluating the safety and tolerability of CY6463, 
TEAE incidence (number and percentage of participants with TEAEs) will be reported for each 

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treatment group for the Safety population. A TEAE is defined as an AE that started on or after 
the administration of randomized study drug through the last day of the Follow-up period.  
10.4.3. 
Exploratory Endpoint(s) 
Plasma and CSF concentration levels of CY6463 will be summarized for the PK population at 
each nominal timepoint on scheduled study visits. Additionally, the following descriptive 
statistics will be presented: number and percentage of participants with values that are below the 
assay’s limit of quantification; geometric mean; and coefficient of variation, calculated as 
100*SD/mean. PK parameters, if available, will also be summarized using descriptive statistics 
for the PK population. 
All other exploratory endpoints will be summarized by treatment group for each assessment 
timepoint using the ITT population. Baseline values used to calculate the change from baseline 
in these endpoints will be defined as the last non-missing assessment prior to the first 
administration of study drug, usually the predose assessment on Day 1. 
Analyses of change from baseline exploratory endpoints will be conducted using the ITT 
population. A mixed-effect model repeated measures (MMRM) analysis with change from 
baseline as the response variable, treatment, visit, and treatment-by-visit interaction as fixed 
effects and the respective baseline value as the covariate with unstructured as the variance-
covariance structure will be performed. Treatment differences between the CY6463 group and 
the placebo group will be estimated for the overall treatment period and at each assessment 
timepoint. Least square means and least square mean differences between the CY6463 group and 
placebo and their aVVRFLDWHG  FRQILGHQFH LQWHUYDOV ZLOO EH SUHVHQWHG Participants who are 
missing both baseline and all treatment period values will be excluded. The missing at random 
assumption of MMRM will be utilized, and no imputation will be performed for missing 
observations. 
The summary and analyses of the non-PK exploratory endpoints will also be performed using the 
PD evaluable population. 
10.4.4. 
Safety Analyses 
All safety analyses will be performed on the Safety population. 
AEs will be coded using the latest version of MedDRA available at the start of the study. TEAEs 
will be summarized for each treatment group by SOC and preferred term (PT), and additionally 
by severity and relationship to study drug. In addition, the incidence of TEAEs leading to 
premature discontinuation of study drug and SAEs will be summarized by treatment group, SOC, 
and PT. Listings of pretreatment AEs, TEAEs, severe TEAEs, AESIs, study drug-related TEAEs, 
SAEs, TEAEs leading to study discontinuation, and AEs leading to death (if any) will be 
provided. 
Descriptive statistics for observed values and changes from baseline values at each assessment 
time point will be presented by treatment group for each clinical laboratory, vital signs, and ECG 
parameters. 

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The number and percentage of participants with suicidal ideation, suicidal behavior, and self-
injurious behavior without suicidal intent will be summarized at each assessment timepoint by 
treatment group.  
10.4.5. 
Other Analyses  
Potential relationships between CY6463 plasma concentrations and PD exploratory assessments 
may be assessed. 
10.5. 
Interim Analyses 
No formal interim analysis is planned for this study. Study data will be reviewed by an unblinded 
DRC as specified in Section 6.3.2.  

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11. 
LIST OF REFERENCES 
1. Global, regional, and national burden of Alzheimer's disease and other dementias, 1990-
2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurol. 
2019;18(1):88-106. 
2. Alzheimer's Association. 2020 Alzheimer's Disease Facts and Figures. Alzheimers 
Dement. 2020;16(3). 
3. Xu J, Zhang Y, Qiu C, Cheng F. Global and regional economic costs of dementia: a 
systematic review. The Lancet. 2017;390:S47. 
4. Venturelli M, Pedrinolla A, Boscolo Galazzo I, Fonte C, Smania N, Tamburin S, et al. 
Impact of nitric oxide bioavailability on the progressive cerebral and peripheral 
circulatory impairments during aging and Alzheimer's disease. Front Physiol. 
2018;9:169. 
5. Iadecola C, Duering M, Hachinski V, Joutel A, Pendlebury ST, Schneider JA, et al. 
Vascular cognitive impairment and dementia: JACC scientific expert panel. J Am Coll 
Cardiol. 2019;73(25):3326-44. 
6. Ben Aissa M, Lee SH, Bennett BM, Thatcher GR. Targeting NO/cGMP signaling in the 
CNS for neurodegeneration and Alzheimer's disease. Curr Med Chem. 
2016;23(24):2770-88. 
7. Garthwaite J. NO as a multimodal transmitter in the brain: discovery and current status. 
Brit J Pharmacol. 2019;176(2):197-211. 
8. McKhann GM, Knopman DS, Chertkow H, Hyman BT, Jack Jr. CR, Kawas CH, et al. 
The diagnosis of dementia due to Alzheimer's disease: Recommendations from the 
National Institute on Aging-Alzheimer's Association workgroups on diagnostic 
guidelines for Alzheimer's disease. Alzheimer's & Dementia. 2011;7(3):263-69. 
9. Fazekas F, Chawluk JB, Alavi A, Hurtig HI, Zimmerman RA. MR signal abnormalities at 
1.5 T in Alzheimer's dementia and normal aging. AJR Am J Roentgenol. 
1987;149(2):351-6. 
10. United States Census Bureau. Decennial Census Official Publications, 2010. Available 
from: https://www.census.gov/programs-surveys/decennial-census/decade/decennial-
publications.2010.html. 
11. Chin AL, Negash S, Hamilton R. Diversity and disparity in dementia: the impact of 
ethnoracial differences in Alzheimer disease. Alzheimer Dis Assoc Disord. 
2011;25(3):187-95. 
12. Barnes LL, Bennett DA. Alzheimer's disease in African Americans: risk factors and 
challenges for the future. Health Aff (Millwood). 2014;33(4):580-6. 
13. Posner K, Brown GK, Stanley B, Brent DA, Yershova KV, Oquendo MA, et al. The 
Columbia-Suicide Severity Rating Scale: initial validity and internal consistency findings 
from three multisite studies with adolescents and adults. Am J Psychiatry. 
2011;168(12):1266-77. 

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14. Highlights of Prescribing Information - ADEMPAS (riciguat) tablets, for oral use 
Whippany, NJ: Bayer HealthCare Pharmaceuticals Inc.; 2018. 
15. Albert MS, DeKosky ST, Dickson D, Dubois B, Feldman HH, Fox NC, et al. The 
diagnosis of mild cognitive impairment due to Alzheimer's disease: recommendations 
from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic 
guidelines for Alzheimer's disease. Alzheimers Dement. 2011;7(3):270-9. 
16. McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM. Clinical 
diagnosis of Alzheimer's disease: report of the NINCDS-ADRDA Work Group under the 
auspices of Department of Health and Human Services Task Force on Alzheimer's 
Disease. Neurology. 1984;34(7):939-44. 

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APPENDIX 1. REGULATORY, ETHICAL, AND STUDY OVERSIGHT 
CONSIDERATIONS 
Direct Access to Source Data/Documents 
Study Monitoring 
Before an investigational site can enter a participant into the study, a representative of the 
sponsor will visit (in person or remotely, as necessary) the investigational study site to: 
x Determine the adequacy of the facilities 
x Discuss with the investigator(s) and other personnel their responsibilities with regard 
to protocol adherence, and the responsibilities of the sponsor or its representatives. 
This will be documented in a clinical study agreement between the sponsor and the 
investigator. 
During the study, a monitor from the sponsor or its representative will have regular contact with 
each study center for the following purposes: 
x Provide information and support to the investigator(s) 
x Confirm that facilities remain acceptable 
x Confirm that the study team is adhering to the protocol, that data are being accurately 
recorded in the eCRFs, and that study drug accountability checks are being performed 
x Perform source data verification. This includes a comparison of the data in the eCRFs 
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, clinic charts). 
x Record and report any protocol deviations not previously sent to the sponsor 
x Confirm AEs and SAEs have been properly documented on CRFs and confirm any 
SAEs have been forwarded to the sponsor and that those SAEs that met criteria for 
regulating reporting have been forwarded to the IRB. 
The monitor will be available between visits if the investigator(s) or other staff needs 
information or advice. 
Audits and Inspections 
Authorized representatives of the sponsor, a regulatory authority, an IEC or an IRB may visit the 
site to perform audits or inspections, including source data verification. The purpose of an audit 
or 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, good clinical practice (GCP) 
guidelines of the ICH, and any applicable regulatory requirements. The investigator should 
contact the sponsor immediately if contacted by a regulatory agency about an inspection. 

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Institutional Review Board (IRB)/Independent Ethics Committee (IEC) 
The principal investigator at each study centers must obtain IRB/IEC approval for the study. 
Initial IRB/IEC approval and all materials approved by the IRB/IEC for this study, including 
participant ICF(s) and recruitment materials, must be maintained by the investigator and made 
available for inspection.  
Quality Control and Quality Assurance 
To ensure compliance with GCP and all applicable regulatory requirements, the sponsor may 
conduct a quality assurance audit. See Audits and Inspections, above. 
Ethics 
Ethics Review 
The final study protocol, including the final version of the ICF(s), must be approved or given a 
favorable opinion in writing by the respective study center’s IRB/IEC. The investigator must 
submit written IRB/IEC approval to the sponsor/sponsor’s designee before enrolling a participant 
into the study. 
The principal investigator of the respective study center is responsible for informing the IRB/IEC 
of any amendment to the protocol in accordance with local requirements. In addition, the 
IRB/IEC must approve all participant-facing materials, including but not limited to advertising 
used to recruit participants for the study. The protocol must be re-approved by the IRB/IEC upon 
receipt of amendments and annually, as local regulations require. 
The principal investigator of a respective study center is also responsible for providing the 
IRB/IEC with reports of any reportable serious adverse drug reactions from any other study 
conducted with the study drug. The sponsor/sponsor’s designee will provide this information to 
the principal investigator. 
Progress reports and notifications of serious adverse drug reactions will be provided to the 
IRB/IEC according to local regulations and guidelines. 
Ethical Study Conduct  
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki and are consistent with ICH/GCP, applicable regulatory requirements 
and sponsor policy. 
Informed Consent  
The principal investigator(s) at each study center will ensure that each participant (and/or LAR 
and the participant's caregiver/study partner, as applicable [see Eligibility Inclusion 1]) is given 
full and adequate oral and written information about the nature, purpose, possible risk and 
benefit of study participation. A participant will not undergo any study procedure unless and 
until both the participant (and/or the participant’s LAR, if applicable) sign the ICF(s). The 
ICF(s) will be written in such a way that at minimum, the LAR and caregiver/study partner, as 
applicable, understand the implications of study participation. The participant (and 

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LAR/caregiver/study partner, as applicable) will be given the opportunity to ask questions and 
allowed time to consider the information provided. Participants must also be notified that they 
are free to discontinue from the study at any time.  
The principal investigator(s) must maintain the original, signed ICF(s). A copy of the signed 
ICF(s) must be given to the participant (and to the LAR/caregiver/study partner, as applicable). 
Participants who are rescreened are required to sign a new ICF. 
Data Handling and Recordkeeping 
Data Protection 
x 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 that would make the participant identifiable will 
not be transferred. 
x The participant must be informed that his/her personal study-related data will be used 
by the sponsor in accordance with local data protection law. The level of disclosure 
must also be explained to the participant who will be required to give consent for 
their data to be used as described in the ICF.  
x The participant must be informed that his/her medical records may be examined by 
the sponsor's quality assurance auditors or other authorized personnel appointed by 
the sponsor, by appropriate IRB/IEC members, and by inspectors from regulatory 
authorities. 
Inspection of Records 
The sponsor or sponsor’s designee will be allowed to conduct site visits to the investigation 
facilities for the purpose of monitoring any aspect of the study. The investigator agrees to allow 
the monitor to inspect the drug storage area, study drug stocks, drug accountability records, 
participant charts and study source documents, and other records relative to study conduct. 
Retention of Records 
Principal investigators must maintain all documentation relating to the conduct of this study for a 
period of 2 years after the last marketing application approval of CY6463 or, if not approved, 
2 years after discontinuance of its development. If it becomes necessary for the sponsor or a 
regulatory authority to review documentation relating to the study, the investigator will permit 
access to such records. 
Publication Policy 
All data generated in this study will be the property of the sponsor. An integrated clinical and 
statistical report will be prepared at the completion of the study. 
Please refer to the study center clinical trial agreement for publication and disclosure 
information. 

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APPENDIX 2. ADVERSE EVENTS, AESIS, AND SAES: DEFINITIONS 
AND PROCEDURES FOR RECORDING AND 
EVALUATING 
Definition of Terms 
Adverse Event (AE) 
Per ICH, AEs are defined as any untoward medical occurrence in a patient or clinical study 
participant administered a pharmaceutical product and which 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.  
Events Meeting the AE Definition 
Ɣ
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or other safety 
assessments (eg, ECG, radiological scans, vital signs measurements), including those that worsen 
from baseline, that are considered clinically significant in the medical and scientific judgment of 
the investigator (ie, not related to progression of underlying disease) 
Ɣ
Exacerbation of a chronic or intermittent pre-existing condition including either an increase in 
frequency and/or intensity of the condition 
Ɣ
New conditions detected or diagnosed after study intervention administration even though it may 
have been present before the start of the study 
Ɣ
Signs, symptoms, or the clinical sequelae of a suspected intervention-intervention interaction 
Ɣ   Signs, symptoms, or the clinical sequelae of a suspected overdose of either study drug or a 
concomitant medication. Overdose per se will not be reported as an AE/SAE unless it is an 
intentional overdose taken with possible suicidal/self-harming intent; such overdoses should be 
reported regardless of sequelae. 
Events NOT Meeting the AE Definition 
Ɣ
Any clinically significant abnormal laboratory findings or other abnormal safety assessments that 
are associated with the underlying disease, unless judged by the investigator to be more severe 
than expected for the participant’s condition 
Ɣ
The disease/disorder being studied or expected progression, signs, or symptoms of the 
disease/disorder being studied, unless more severe than expected for the participant’s condition 
Ɣ
Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to the 
procedure is the AE 
Ɣ
Situations in which an untoward medical occurrence did not occur (social and/or convenience 
admission to a hospital) 
Ɣ
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or detected at 
the start of the study that do not worsen 

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Serious Adverse Event (SAE) 
An SAE is an AE occurring during any study phase (ie, at baseline or during Treatment, 
washout, or Follow-up), and at any dose of study drug that fulfills 1 or more of the following: 
x Results in death  
x Is immediately life-threatening (The term “life-threatening” refers to an event in 
which the participant was at risk of death at the time of the event. It does not refer to 
an event that hypothetically might have caused death if it were more severe.) 
x Requires inpatient hospitalization or prolongation of existing hospitalization  
x Results in persistent or significant disability or incapacity: a substantial disruption of 
a person’s ability to conduct normal life functions  
x Results in a congenital abnormality or birth defect 
x Is an important medical event that may require medical intervention to prevent 1 of 
the outcomes listed above.  
Adverse Events of Special Interest (AESIs) 
Based on the mechanism of action of sGC and anticipated vasodilation effects and based on the 
fact that CY6463 is a CNS-penetrant stimulator of sGC, the sponsor will collect AESIs in a 
timely manner. The AESIs relate to symptomatic hypotensive events and/or tachycardia, 
dizziness, syncope, and TEAEs related to change of neurobehaviors (ie, suicidality or euphoria).  
In addition, because the marketed sGC stimulator riociguat includes bleeding events as a warning 
and precaution on its prescribing information (14), bleeding events will also be considered 
AESIs for CY6463 in this study. The specific list of AESI terms will be provided in the safety 
management plan.  
An AESI classification means that although an event might be nonserious, it will nonetheless be 
reported to the sponsor by completing the AE eCRF and filling in the AESI box within 
5 business days of the investigator’s first awareness of the AESI event. 
Treatment-Emergent Adverse Event (TEAE) 
A TEAE is defined as an AE that started on or after the administration of randomized study drug 
through the last day of the Follow-up period. 
Recording of AEs and/or SAEs 
When an AE/SAE occurs, it is the responsibility of the investigator to review all documentation 
(eg, hospital progress notes, laboratory reports, and diagnostics reports) related to the event. The 
investigator will then record all relevant information in the AE eCRF page. 
x It is not acceptable for the investigator to send photocopies of the participant’s 
medical records in lieu of completion of the AE eCRF. 
x There may be instances when copies of medical records for certain cases are 
requested by the Safety CRO. In this case, all participant identifiers, with the 

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exception of the participant number, will be redacted on the copies of the medical 
records before submission to the Safety CRO. 
AE terms should be reported in standard medical terminology when possible. For each AE, the 
investigator will evaluate the event based on signs, symptoms, and/or other clinical information 
Whenever possible, the diagnosis (not the individual signs/symptoms) will be documented as the 
AE/SAE. The investigator will complete the AE CRF in its entirety, including details regarding 
event onset (date and time), resolution (date and time), intensity, causality, action taken, serious 
outcome (if applicable), whether or not any medications were given in response to the event and 
whether or not the event caused the participant to discontinue the study. 
Assessment of Intensity 
Intensity will be assessed by the investigator according to the following scale: 
x Mild: An event that is easily tolerated by the participant, causing minimal discomfort 
and not interfering with everyday activities 
x Moderate: An event that causes discomfort sufficient to interfere with normal 
everyday activities 
x Severe: An event that prevents normal everyday activities 
It is important to distinguish between serious and severe AEs. Severity is a measure of intensity 
whereas seriousness is defined by the criteria of this Appendix. An AE of severe intensity may or 
may not be considered serious. 
Relationship to Study Drug 
For all AEs, the investigator must provide an assessment of causal relationship to study drug. 
The causality assessment will be recorded in the participant’s source documentation and on the 
AE eCRF. The investigator may change his/her opinion of causality in light of follow-up 
information and amend the eCRF with the updated causality assessment. 
Causal relationship will be assessed according to the criteria below. 
Related: 
An event where there is at least a reasonable possibility of a causal relationship 
between the event and the study drug. “Reasonable possibility” means there is 
evidence to suggest a potential causal relationship between the drug and the 
event. 
Unrelated: 
Any other event 

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APPENDIX 3. PROHIBITED MEDICATIONS, FOODS, AND 
SUPPLEMENTS 
Also see Lifestyle Restrictions (Section 7.5) and Concomitant Medications and Therapies 
(Section 8.7).  
Use of the following is prohibited from the Screening visit through the Follow-up visit, unless noted 
otherwise below: 
x 
Specific inhibitors of PDE5, including sildenafil, tadalafil, vardenafil 
x 
Nonspecific inhibitors of PDE5, including dipyridamole, theophylline  
x 
Any supplement for the treatment of erectile dysfunction 
x 
Other sGC stimulators, including riociguat and vericiguat 
x 
Nitrates such as nitroglycerin, isosorbide mononitrate, isosorbide dinitrate, sodium 
nitroprusside, amyl nitrate  
x 
$VSLULQ  mg/day 
x 
Any anticoagulant medication 
x 
Any P2Y12 inhibitor, including cangrelor, clopidogrel, prasugrel, ticagrelor, ticlopidine 
x 
Use of any “illicit drug” is not permitted beginning 1 month before Screening through the 
Follow-up visit 
Note: Medical (prescribed) cannabis and cannabidiol products are permitted except for 
24 hours before the Screening, Day 1 and EoT visits, and for 4 hours prior to all other study 
visits. 

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APPENDIX 4. NATIONAL INSTITUTE ON AGING / ALZHEIMER’S 
ASSOCIATION CRITERIA FOR AD DEMENTIA 
Source:  
   McKhann GM, Knopman DS, Chertkow H, Hyman BT, Jack Jr. CR, Kawas CH, et al. The diagnosis of 
dementia due to Alzheimer's disease: Recommendations from the National Institute on Aging-Alzheimer's 
Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimer's & Dementia. 
2011;7(3):263-69. doi:10.1016/j.jalz.2011.03.005A 
All-Cause Dementia: Core Clinical Criteria 
The diagnosis of dementia is intended to encompass the spectrum of severity, ranging from the 
mildest to the most severe stages of dementia. The methodology for staging of dementia severity 
was beyond the charge of the workgroup. Dementia is diagnosed when there are cognitive or 
behavioral (neuropsychiatric) symptoms that: 
1. Interfere with the ability to function at work or at usual activities; and 
2. Represent a decline from previous levels of functioning and performing; and 
3. Are not explained by delirium or major psychiatric disorder; 
4. Cognitive impairment is detected and diagnosed through a combination of (1) history-
taking from the patient and a knowledgeable informant and (2) an objective cognitive 
assessment, either a “bedside” mental status examination or neuropsychological testing. 
Neuropsychological testing should be performed when the routine history and bedside 
mental status examination cannot provide a confident diagnosis. 
5. The cognitive or behavioral impairment involves a minimum of 2 of the following 
domains: 
a. Impaired ability to acquire and remember new information—symptoms include: 
repetitive questions or conversations, misplacing personal belongings, forgetting 
events or appointments, getting lost on a familiar route. 
b. Impaired reasoning and handling of complex tasks, poor judgment—symptoms 
include: poor understanding of safety risks, inability to manage finances, poor 
decision-making ability, inability to plan complex or sequential activities. 
c. Impaired visuospatial abilities—symptoms include: inability to recognize faces or 
common objects or to find objects in direct view despite good acuity, inability to 
operate simple implements, or orient clothing to the body. 
d. Impaired language functions (speaking, reading, writing)—symptoms include: 
difficulty thinking of common words while speaking, hesitations; speech, spelling, 
and writing errors. 
e. Changes in personality, behavior, or comportment—symptoms include: 
uncharacteristic mood fluctuations such as agitation, impaired motivation, initiative, 
apathy, loss of drive, social withdrawal, decreased interest in previous activities, loss 
of empathy, compulsive or obsessive behaviors, socially unacceptable behaviors. 
The differentiation of dementia from mild cognitive impairment (see Albert et al 2011 (15) on 
the diagnosis of mild cognitive impairment) rests on the determination of whether or not there is 
significant interference in the ability to function at work or in usual daily activities. This is 

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inherently a clinical judgment made by a skilled clinician on the basis of the individual 
circumstances of the patient and the description of daily affairs of the patient obtained from the 
patient and from a knowledgeable informant. 
Probable AD Dementia: Core Clinical Criteria 
Probable AD dementia is diagnosed when the individual: 
1. Meets criteria for all-cause dementia described above, and in addition, has the following 
characteristics: 
a. Insidious onset. Symptoms have a gradual onset over months to years, not sudden 
over hours or days; 
b. Clear-cut history of worsening of cognition by report or observation; and 
c. The initial and most prominent cognitive deficits are evident on history and 
examination in 1 of the following categories. 
x Amnestic presentation: It is the most common syndromic presentation of AD 
dementia. The deficits should include impairment in learning and recall of recently 
learned information. There should also be evidence of cognitive dysfunction in at 
least 1 other cognitive domain, as defined above.  
x Nonamnestic presentations: 
 Language presentation: The most prominent deficits are in word-finding, but 
deficits in other cognitive domains should be present. 
 Visuospatial presentation: The most prominent deficits are in spatial cognition, 
including object agnosia, impaired face recognition, simultanagnosia, and alexia. 
Deficits in other cognitive domains should be present. 
 Executive dysfunction: The most prominent deficits are impaired reasoning, 
judgment, and problem solving. Deficits in other cognitive domains should be 
present. 
d. The diagnosis of probable AD dementia should not be applied when there is evidence 
of (a) substantial concomitant cerebrovascular disease, defined by a history of a 
stroke temporally related to the onset or worsening of cognitive impairment; or the 
presence of multiple or extensive infarcts or severe white matter hyperintensity 
burden; or (b) core features of Dementia with Lewy bodies other than dementia itself; 
or (c) prominent features of behavioral variant frontotemporal dementia; or 
(d) prominent features of semantic variant primary progressive aphasia or 
nonfluent/agrammatic variant primary progressive aphasia; or (e) evidence for 
another concurrent, active neurological disease, or a non-neurological medical 
comorbidity or use of medication that could have a substantial effect on cognition. 
 
Note: All patients who met criteria for “probable AD” by the 1984 NINCDS-ADRDA (National 
Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer’s Disease 
and Related Disorders Association) criteria (16) would meet the McKhann 2011 (8) criteria for 
probable AD dementia. 

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APPENDIX 5. SPONSOR’S SIGNATURE PAGE 
 
Sponsor’s Approval 
The protocol has been approved by Cyclerion Therapeutics, Inc. 
 
 
Sponsor’s Authorized Officer: 
 
 
 
 
 

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APPENDIX 6. INVESTIGATOR’S AGREEMENT 
 
I have received and read the Investigator’s Brochure for CY6463. I have also read the 
C6463-202 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 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Center Name (please print)