A Phase 2b, Randomized, Double-blind, Placebo-controlled, Multiple Dose, Biomarker and Safety Study of PTI-125 in Mild-to-moderate Alzheimer's Disease Patients
Phase: PHASE2
Conditions: Alzheimer Disease
Sponsor: Cassava Sciences, Inc.

 
Cassava Sciences, Inc. 
Clinical Protocol PTI-125-02 
PTI-125, a small molecule to treat AD 
June 28, 2019 
 
Page 1 of 33 
 
 
 
 
CONFIDENTIAL 
 
 
 
CLINICAL RESEARCH PROTOCOL 
PROTOCOL PTl-125-02 
 
A Phase 2b, Randomized, Double-blind, Placebo-controlled,  
Multiple Dose, Biomarker and Safety Study  
of PTl-125 in Mild-to-moderate Alzheimer’s Disease Patients 
 
 
Sponsor:  
 
 
 
Cassava Sciences, Inc. 
7801 N. Capital of Texas Hwy, Ste. 260 
Austin, TX 78731 
Phone: 
512-501-1900 
 
Study Monitor: 
Nadav Friedmann, PhD, MD 
Chief Operating & Medical Officer  
Phone: 925-788-4585 
Email: nfriedmann@cassavasciences.com 
 
Project Manager 
Michael Marsman, PharmD 
 
Regulatory Affairs and QA 
 
Phone:    512-562-2173 
 
Email:     mmarsman@cassavasciences.com 
 
Protocol Date: 
June 28, 2019 
 
This clinical trial is funded by NIH grant AG060878. 
 
Confidentiality 
The information contained in this document and all information provided to you related 
to PTl-125 ("Drug") are the confidential and proprietary information of Cassava 
Sciences, Inc. (CSI) and except as may be required by federal, state, or local laws or 
regulations, may not be disclosed to others without prior written permission of CSI. 
The Principal Investigator may, however, disclose such information to supervised 
individuals working on the Drug, provided such individuals agree to be bound to 
maintain the confidentiality of such Drug information. 

 
Cassava Sciences, Inc. 
Clinical Protocol PTI-125-02 
PTI-125, a novel small molecule for AD 
June 28, 2019 
 
Page 3 of 33 
 
 
 
 
CONFIDENTIAL 
 
 
Cassava Sciences, Inc. 
CLINICAL RESEARCH PROTOCOL 
 
 
 
 
A Phase 2b, Randomized, Double-blind, Placebo-controlled,  
Multiple Dose, Biomarker and Safety Study  
of PTl-125 in Mild-to-moderate AD patients 
 
 
 
 
 
Signature of Agreement for Protocol PTI-125-02 
 
 
 
I have read this protocol and agree to conduct the study as outlined herein, in 
accordance with Good Clinical Practice (GCP) and complying with the obligations 
and requirements of clinical investigators and all other requirements listed in 21 
CFR part 312. 
 
 
 
 
 
 
 
 
Principal Investigator Signature 
Date 
 
 
 
 
 
 
Print Principal Investigator Name and Title 

 
Cassava Sciences, Inc. 
Clinical Protocol PTI-125-02 
PTI-125, a novel small molecule for AD 
June 28, 2019 
Page 4 of 33 
 
 
 
 
CONFIDENTIAL 
 
Table of Contents 
1. 
List of abbreviations ................................................................................................. 6 
2. 
INTRODUCTION .................................................................................................... 8 
3. 
STUDY OBJECTIVES ............................................................................................. 12 
4. 
SUMMARY OF STUDY DESIGN .......................................................................... 12 
5. 
SUBJECT SELECTION ........................................................................................... 13 
5.1. Study Population ........................................................................................................... 13 
5.2. Inclusion Criteria ........................................................................................................... 13 
5.3. Exclusion Criteria .......................................................................................................... 14 
6. 
STUDY DRUG ...................................................................................................... 17 
6.1. PTI-125 Physical Description and Preparation.................................................................. 17 
6.1.1. Storage ............................................................................................................... 17 
6.1.2. Drug Accountability ............................................................................................ 17 
6.2. Administration and Dosing Regimen .............................................................................. 17 
6.3. Concomitant Medications ................................................................................................. 17 
7. 
STUDY PROCEDURES .......................................................................................... 17 
7.1. Liver chemistry stopping criteria ..................................................................................... 18 
7.2. Evaluations by Visit ....................................................................................................... 18 
7.2.1. Screening Visit 1 (No longer than 30 days prior to Day 1) ................................. 18 
7.2.2. Screening Visit 2 (If all Screening Visit 1 criteria are met) .................................. 19 
7.2.3. Study Day 1 (Dosing Initiation) .......................................................................... 19 
7.2.4. Day 7 Follow-up Visit ......................................................................................... 20 
7.2.5. Day 14 Follow-up Visit ....................................................................................... 20 
7.2.6. Day 28 Follow-up Visit ....................................................................................... 20 
7.2.7. End-of-study Follow-up ...................................................................................... 21 
7.2.8. Unscheduled Visits and Discontinuation due to AEs ......................................... 21 
7.3. Laboratory Assessments ................................................................................................. 21 
7.3.1. Clinical Laboratory Tests .................................................................................... 21 
7.3.2. Preparation of Whole Blood Samples for biomarkers and APOE genotyping ..... 22 
7.3.3. Preparation of Plasma Samples for Pharmacokinetic Determination .................. 22 
7.3.4. CSF assays ........................................................................................................ 22 
8. 
EARLY DISCONTINUATION ................................................................................. 23 
9. 
ADVERSE EVENTS/SERIOUS ADVERSE EVENTS ................................................. 24 
9.1. Adverse Events - Definition ............................................................................................. 24 
9.2. Adverse Events - Severity Rating .................................................................................... 25 

 
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Clinical Protocol PTI-125-02 
PTI-125, a novel small molecule for AD 
June 28, 2019 
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CONFIDENTIAL 
 
9.3. Adverse  Events  -  Relationship to  Study Drug .................................................................. 25 
9.4. Serious Adverse Events and Unexpected Adverse Events - Definitions ............................... 25 
9.5. Serious Adverse Events Reporting ................................................................................... 26 
10. 
STATISTICAL CONSIDERATIONS ......................................................................... 27 
10.1. Randomization .............................................................................................................. 27 
10.2. Analysis Populations ...................................................................................................... 27 
10.3. Pharmacokinetic Parameters ........................................................................................... 27 
10.4. Statistical Analysis ......................................................................................................... 28 
10.5. Safety Analysis .............................................................................................................. 28 
10.6. Sample Size .................................................................................................................. 28 
11. 
STUDY TERMINATION ......................................................................................... 28 
12. 
DATA COLLECTION, RETENTION AND MONITORING ........................................ 28 
12.1. Case Report Forms ......................................................................................................... 28 
12.2. Availability and Retention of Investigational Records ....................................................... 29 
12.3. Subject Confidentiality ................................................................................................... 29 
12.4. Liability ........................................................................................................................ 29 
12.5. Ethical and Legal Issues ................................................................................................. 30 
12.5.1. Institutional Review Board .................................................................................. 30 
12.6. Informed Consent Form .................................................................................................. 30 
13. 
INVESTIGATOR RESPONSIBILITIES ................................................................... 31 
14. 
REFERENCES ...................................................................................................... 32 
15. 
Appendix A – Schedule of Activities ........................................................................ 33 
 
 
 
 
 
 

Cassava Sciences, Inc. 
Clinical Protocol PTI-125-02 
PTI-125, a small molecule to treat AD 
June 28, 2019 
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CONFIDENTIAL 
1. LIST OF ABBREVIATIONS 
7nAChR  
 
 
7 nicotinic acetylcholine receptor 
A42 
 
 
 
amyloid beta1-42 
AChEI  
 
 
acetylcholinesterase inhibitor 
AD 
 
 
 
Alzheimer’s disease 
ADME 
 
 
absorption, distribution, metabolism, excretion 
AE 
 
 
 
adverse event 
ALT   
 
 
alanine transaminase 
ALP 
 
 
 
alkaline phosphatase 
ANOVA 
 
 
analysis of variance 
AST   
 
 
aspartate transaminase 
AUC  
 
 
area under the curve 
BUN  
 
 
blood urea nitrogen 
CFR 
 
 
 
Code of Federal Regulations 
Cmax  
 
 
maximum plasma concentration 
CRO  
 
 
contract research organization 
CSF 
 
 
 
cerebrospinal fluid 
CSI 
 
 
 
Cassava Sciences, Inc. 
C-SSRS 
 
 
Columbia-Suicide Severity Rating Scale 
CT 
 
 
 
computed tomography 
DSMB/DMC  
 
Data Safety Monitoring Board/Data Monitoring Committee 
ECG  
 
 
electrocardiogram 
eCRF  
 
 
electronic case report form 
EDTA  
 
 
ethylenediaminetetraacetic acid 
FDA  
 
 
Federal Drug Association 
FIH 
 
 
 
first in human 
FLNA  
 
 
filamin A 
GCP  
 
 
good clinical practice 
GGT   
 
 
gamma glutamyl transpeptidase 
GLP 
 
 
 
good laboratory practice 
HBsAg  
 
 
hepatitis B surface antigen 
HCV  
 
 
hepatitis C virus 
HIV 
 
 
 
human immunodeficiency virus 
hERG  
 
 
human ether-a-go-go-related gene 
IB 
 
 
 
Investigator’s Brochure 
ICF 
informed consent form 
ICH 
International Council on Harmonization of Technical 
Requirements for Registration of Pharmaceuticals for Human 
Use 
IR 
 
 
 
insulin receptor 
IRB 
 
 
 
independent review board 
ISLT  
 
 
International Shopping List Test 
LDH   
 
 
lactose dehydrogenase 

Cassava Sciences, Inc. 
Clinical Protocol PTI-125-02 
PTI-125, a small molecule to treat AD 
June 28, 2019 
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CONFIDENTIAL 
LOQ  
 
 
limit of quantitation 
MMSE 
 
 
Mini-Mental State Examination 
MRI 
 
 
 
magnetic resonance imaging 
mTOR  
 
 
mammalian target of rapamycin 
NMDAR 
 
 
N-methyl D-aspartate receptor 
NOAEL 
 
 
no observable adverse effect level 
NOEL  
 
 
no observable effect level 
PK 
 
 
 
pharmacokinetics 
PTI-125 
 
 
small molecule drug candidate to treat AD 
PTI-125Dx 
 
 
blood-based diagnostic/biomarker candidate 
RBC  
 
 
red blood cell 
SAE 
 
 
 
serious adverse event 
SOP 
 
 
 
standard operating procedure 
Tmax  
 
 
time to Cmax 
ULN  
 
 
upper limit of normal 
WBC  
 
 
white blood cell 
YKL40 
chitinase-like protein 1, a secreted glycoprotein associated with 
inflammation and tissue remodeling  
 
 

Cassava Sciences, Inc. 
Clinical Protocol PTI-125-02 
PTI-125, a small molecule to treat AD 
June 28, 2019 
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CONFIDENTIAL 
 
2. INTRODUCTION 
Cassava Sciences Inc. (CSI) is developing PTI-125, a novel drug candidate designed to 
treat and slow the progression of Alzheimer’s disease (AD). PTI-125 binds with 
femtomolar affinity to an altered conformation of filamin A (FLNA) that is induced by 
beta amyloid1-42 (A42), present in AD brain and critical to the toxicity of A42.1-3 PTI-
125 binding reverses the altered FLNA conformation and restores FLNA’s native shape, 
preventing two toxic signaling cascades of A42. A42, in monomer or small oligomer 
form, hijacks the 7-nicotinic acetylcholine receptor (7nAChR) and signals via this 
receptor to hyperphosphorylate tau, and this signaling requires the recruitment of altered 
FLNA to this receptor. Second, altered FLNA associates with toll-like receptor 4 (TLR4) 
to allow A42 to persistently activate this receptor. Normal FLNA does not associate with 
either 7nAChR or TLR4. In addition to disrupting the normal functions of 7nAChR 
and tau protein, A42’s toxic signaling to hyperphosphorylate tau leads to the signature 
tangles and plaques found in brains of AD patients. In two AD mouse models and in 
postmortem human AD brain tissue, PTI-125 restored function of three receptors that are 
impaired in AD: the 7nAChR, the N-methyl-D-aspartate receptor (NMDAR), and the 
insulin receptor (IR).2,3 PTI-125 also reduced tau hyperphosphorylation, amyloid 
deposits, neurofibrillary tangles and inflammatory cytokine release.2,3 We therefore 
expect PTI-125 to improve memory and to slow or halt AD progression. Both mouse 
models used a dose of 20 mg/kg/day (equivalent to 60 mg/m2/day).  
A robust nonclinical ADME, safety pharmacology, and general and genetic toxicology 
program has been carried out with PTI-125. In vitro metabolic profiling showed minimal 
metabolism across several species including humans. PTI-125 was rapidly absorbed and 
eliminated in in vivo studies in rat and dog with nearly 100% oral bioavailability, a 2.67-h 
half-life in dog, dose-proportional PK and no accumulation. Safety pharmacology studies 
showed no adverse effects on gross behavioral and physiological parameters in the Irwin 
test of CNS toxicity in rats, no adverse effects on respiratory rate, tidal volume or minute 
volume in the rat respiratory test, and no adverse effects on arterial blood pressure, heart 
rate and ECG parameters in the dog cardiovascular study. The in vitro hERG test for 
cardiotoxicity also indicated no adverse effect. A full battery of genotoxicity studies was 
conducted (in vitro bacterial Ames, in vitro chromosomal aberration, and in vivo rat 
micronucleus test) and were all negative. An in vitro specificity screen showed no 
significant activation or inhibition of a panel of 68 receptors, channels and transporters.  
PTI-125 was tested in single dose and repeat dose oral toxicity studies in rats and dogs. In 
a 28-day repeat dose oral toxicity study followed by a 28-day drug-free recovery period in 
rats (PTI-125-NC-040) with PTI-125 dose levels up to and including 1000 mg/kg/day 
(equivalent to 6,000 mg/m2), toxicity was mainly characterized at 1000 mg/kg/day by a 
decrease in mean body weight, which continued during the recovery period. A diffuse 
cellular hypertrophy of the liver was seen at 1000 mg/kg/day in males and females and 
was interpreted as an adaptive response to the test article. A no-observed-effect-level 

Cassava Sciences, Inc. 
Clinical Protocol PTI-125-02 
PTI-125, a small molecule to treat AD 
June 28, 2019 
Page 9 of 33 
 
 
 
 
CONFIDENTIAL 
(NOEL) could not be determined and the no-observed-adverse-effect-level (NOAEL) was 
determined to be 500 mg/kg/day (equivalent to 3,000 mg/m2). Safety margins based on 
this study are shown in Table 1. 
Table 1.  Safety Margin for a 100 mg b.i.d. Human Dose Based on the 4-week Rat Tox  
a Mean exposure for male and female rats combined on last day of study 
b Mean exposure for patients after 100 mg b.i.d. dose of PTI-125 on Day 28 (CSR PTI-125-03) 
A 28-day repeat dose oral toxicity study in dogs that included a 28-day drug-free recovery 
period used PTI-125 dose levels up to and including 200 mg/kg/day (equivalent to 4,000 
mg/m2). Findings included slight muscle fasciculations in some animals at the high dose 
only, an increase in blood pressure in high dose females, and sporadic alterations in 
clinical chemistry profiles at the high dose. All observations resolved during the recovery 
period. A NOEL could not be determined, and the NOAEL was determined to be 100 
mg/kg/day (equivalent to 2,000 mg/m2). Safety margins based on this study are shown in 
Table 2. 
Table 2.  Safety Margin for a 100 mg b.i.d. Human Dose Based on the 4-week Dog Tox  
a Mean exposure for male and female dogs combined on last day of study 
b Mean exposure for patients after 100 mg b.i.d. dose of PTI-125 on Day 28 (CSR PTI-125-03) 
A subsequent 13-week repeat dose oral toxicity study with a 28-day recovery in dogs used 
doses of 25, 75 and 150 mg/kg/day. The toxicological response was characterized 
primarily by increased incidence of emesis and salivation (sometimes extreme), and 
decreased food consumption in 150 mg/kg animals (reversible). There were occasional 
incidences of muscle fasciculations, and a few isolated incidences of tremors, lying down, 
reluctance to stand, and hypoactivity (generally slight). Based the severity and time 
course of these observations, the NOAEL was established at 150 mg/kg/day. The Day 90 
Cmax at this dose was 70.3 and 71.8 µg/mL in males and females, respectively, and the 
Day 90 AUClast was 456 and 439 h•µg/mL in males and females, respectively. Safety 
NOAEL 
(mg/kg) 
Cmax (ng/mL) 
AUClast (hr*ng/mL) 
Rat-to-Human Ratio  
(Safety Margin) 
Rata 
Humanb 
Rata 
Humanb 
Cmax 
AUC0-24 
500 
44,900 
1,104 
249,000 
8,483 
40.7 
29.4 
NOAEL 
(mg/kg) 
Cmax (ng/mL) 
AUClast (hr*ng/mL) 
Dog-to-Human Ratio  
(Safety Margin) 
Doga 
Humanb 
Doga 
Humanb 
Cmax 
AUC0-24 
100 
49,000 
1,104 
214,000 
8,483 
44.4 
25.2 

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Clinical Protocol PTI-125-02 
PTI-125, a small molecule to treat AD 
June 28, 2019 
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CONFIDENTIAL 
margins based on this study are shown in Table 3. 
Table 3.  Safety Margin for a 100 mg b.i.d. Human Dose Based on the 13-week Dog Tox  
a Mean exposure for male and female dogs combined on last day of study 
b Mean exposure for patients after 100 mg b.i.d. dose of PTI-125 on Day 28 (CSR PTI-125-03) 
It should be noted that in a 7-day non-GLP dose-range finding study in dogs, convulsions 
(rated “slight”) were observed in one of six animals administered 300 mg/kg/day on Days 
2 and 3. None of the six 1000 mg/kg animals exhibited convulsions. On Day 4, the mid 
(300 mg/kg) and high (1000 mg/kg) doses were reduced to 150 and 200 mg/kg/day, 
respectively.  
A subsequent 6-month repeat dose oral toxicity study in rat (PTI-125-NC-049) used the 
same doses as the 28-day study (50, 500 and 1000 mg/kg/day). The toxicological 
response was characterized by decreased body weights and adverse structural and 
functional alterations in the liver of 500 and 1000 mg/kg animals, including increased 
weight, hepatocellular hypertrophy and vacuolation, single/multiple basophilic/ 
eosinophilic/clear cell focus, hepatocellular degeneration, pigmentation, and oval cell 
hyperplasia. The presence of bile pigment was consistent with cholestasis. These findings 
correlated with changes to the clinical chemistry profile, including increased ALP and 
total/direct bilirubin. Over the 1-month recovery period, there was complete recovery of 
the hepatocellular degeneration and partial recovery of hepatocellular hypertrophy. The 
NOAEL from this 6-month study was 50 mg/kg/day (equivalent to 300 mg/m2). Safety 
margins based on this study are shown in Table 4. 
Table 4.  Safety Margin for a 100 mg b.i.d. Human Dose Based on the 6-month Rat Tox  
a Mean exposure for male and female rats combined on last day of study 
b Mean exposure for patients after 100 mg b.i.d. dose of PTI-125 on Day 28 (CSR PTI-125-03) 
A second 6-month repeat dose oral toxicity study in rat has been initiated with the goal of 
determining a more accurate NOAEL. Doses are vehicle and 125 and 250 mg/kg/day.  
NOAEL 
(mg/kg) 
Cmax (ng/mL) 
AUClast (hr*ng/mL) 
Dog-to-Human Ratio  
(Safety Margin) 
Doga 
Humanb 
Doga 
Humanb 
Cmax 
AUC0-24 
150 
71,100 
1,104 
447,000 
8,483 
64.3 
52.7 
NOAEL 
(mg/kg) 
Cmax (ng/mL) 
AUClast (hr*ng/mL) 
Rat-to-Human Ratio  
(Safety Margin) 
Rata 
Humanb 
Rata 
Humanb 
Cmax 
AUC0-24 
50 
6,240 
1,104 
21,200 
8,483 
5.7 
2.5 

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Clinical Protocol PTI-125-02 
PTI-125, a small molecule to treat AD 
June 28, 2019 
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CONFIDENTIAL 
A 9-month toxicity study in dog has been completed and is awaiting pathology. This 
study started with 200 mg/kg/day as the high dose, which was reduced after 1 month to 
150 mg/kg/day due to a decrease in body weight that was considered unsustainable for 9 
months. Based on clinical signs, clinical chemistry, body weights and food consumption, 
the 150 mg/kg/day dose is estimated to be the NOAEL for this study until pathology is 
complete. 
A first-in-human (FIH) double-blind, Single Ascending Dose clinical trial was conducted 
in healthy normal volunteers, age 18-45 with oral dosing solution. Doses were placebo, 
50, 100 and 200 mg (equivalent to 31, 62, and 123 mg/m2, respectively) administered to 
three different groups of volunteers. The study showed dose proportional PK, and there 
were no drug-related adverse events (AEs). 
A 28-day study was conducted with mild-to-moderate AD patients, receiving PTI-125 
100 mg b.i.d. as oral tablets. Key inclusion criteria were MMSE ≥ 16 and ≤ 24, age 50-
85, and a CSF total tau/Aβ42 ratio ≥ 0.30. CSF samples were collected at screening and 
Day 28. Nine CSF biomarkers were analyzed using commercially available ELISA kits. 
PTI-125 was safe and well tolerated in all patients. All 8 biomarkers that are elevated in 
AD were significantly reduced (Table 5 and Figure 1). Aβ42, which is low in AD, was 
increased slightly but non-significantly. Reduced neuroinflammation was indicated by 
reductions in inflammatory cytokines and YKL-40. A reduced neurodegenerative drive 
was suggested by reductions in neurogranin, neurofilament light chain, and total tau. 
Finally, the robust reduction in phospho-tau (pT181) confirms the mechanism of action of 
PTI-125. 
Table 5   Reductions in CSF biomarkers after 28 days PTI-125 (100 mg, b.i.d.) 
 
Neurogranin 
Neurofilament 
Light Chain 
Total 
Tau 
P-Tau 
(T181) 
Aβ42 
YKL40 
IL-6 
IL-1β 
TNF-α 
Percent
Change 
-32.1% 
-21.5% 
-19.8% 
-34.4% 
4.3% 
-9.4% 
-14.3% 
-11.1% 
-5.1% 
P 
value* 
p < 0.00001 
p < 0.00001 
p < 
0.00001 
p < 
0.00001 
N.S. 
p = 0.043 
p < 
0.00001 
p < 
0.00001 
p < 0.001 
*Screening vs. Day 28, paired t test 
 
 
 
 
 

Cassava Sciences, Inc. 
Clinical Protocol PTI-125-02 
PTI-125, a small molecule to treat AD 
June 28, 2019 
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CONFIDENTIAL 
Fig. 1   Mean Change from Baseline to Day 28 in CSF biomarkers (±SEM) 
 
3. STUDY OBJECTIVES 
The objectives of this study are to investigate the safety and effect on biomarkers and 
cognition of PTI-125 following 1-month, repeat-dose oral administration in mild-to-
moderate AD patients, 50-85 years of age, with MMSE  ≥ 16 and ≤ 26. A second 
objective is to replicate the effects on biomarkers shown in the previous open-label 1-
month study (PTI-125-03). A third objective is to investigate a dose-response of PTI-125. 
4. SUMMARY OF STUDY DESIGN 
This is a Phase 2b, multi-center, randomized, double-blind, placebo-controlled, study 
of PTI-125 in mild-to-moderate AD patients, 50-85 years of age. Approximately sixty 
(60) patients will be enrolled into the study and randomized to one of three cohorts. 
Cohorts will receive placebo or PTI-125 at 50 or 100 mg b.i.d. (n=20 per group). 
Placebo or PTI-125 will be administered as coated tablets. 
There will be two screening visits within 30 days of start of the study. Patients meeting 
initial screening criteria, including a Mini-Mental State Examination (MMSE) score ≥ 16 
and ≤ 26 will return for a CSF draw at a second screening visit to confirm that the Aβ/tau 
Index is indicative of AD (final inclusion criterion). This CSF sample will also serve as 
baseline measurement for the YKL40 neuroinflammation and other potential CSF 
biomarker assays. Cambridge Cognition testing will be conducted at the second screening 
visit, Day 1, and at the end of the study. Patients will be assessed for suicidality via the 
Columbia Suicide Severity Scale (C-SSRS) during the first and last visits. 

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PTI-125, a small molecule to treat AD 
June 28, 2019 
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Patients will report to clinic the morning of Day 1. The following will be conducted 
prior to dosing: Cambridge Cognition testing, a full physical exam, an ECG and a blood 
draw for clinical labs and biomarkers (PTI-125Dx and mTOR). After dosing, patients 
will be monitored for adverse events and vital signs will be taken through 4 h. 
Patients will return to the clinic on Days 7, 14 and 28. 
PK blood samples will be obtained prior to the first dose on Day 14 for Cmin values. On 
Day 28, there will be a CSF draw after the last dose, and an additional PK blood sample 
will be obtained after this CSF draw for calculation of CSF/plasma ratio.  
Blood draws for clinical laboratory testing will be performed at screening and on Days 1, 
7, 14 and 28. Safety assessments of vital signs and listening to heart and lungs will be 
conducted at all visits. ECGs will be conducted on Days 7, 14 and 28.  
Blood samples for testing in PTI-125Dx, the companion diagnostic/biomarker, mTOR 
activation and other potential blood-based biomarkers will be drawn on Day 1 and Day 
28. The Day 28 blood sample will also be used for APOE genotyping. A CSF sample 
collection will be performed on Day 28 for neurogranin, neurofilament light chain, total 
tau, pTau (T181), Aβ42, Aβ40, YKL40, IL-6, IL-1β, TNFα and other potential CSF 
biomarker assays as well as bioanalysis of PTI-125. 
An 
independent 
Data 
Safety Monitoring Board/Data Monitoring Committee 
(DSMB/DMC) has been established and will meet periodically to review patient safety 
assessments and determine if dosing may continue. 
5. SUBJECT SELECTION 
5.1. STUDY POPULATION 
Approximately sixty (60) patients will be enrolled in the study (male and female). 
Dropouts may be replaced at the discretion of Sponsor. 
5.2. INCLUSION CRITERIA 
Each patient must comply with the following Inclusion Criteria:  
1. Ages ≥ 50 and ≤ 85 years 
2. Informed consent form (ICF) signed by the subject or legally acceptable 
representative. If a legally acceptable representative signs the ICF, a notation of 
capacity of the subject must be noted. 

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PTI-125, a small molecule to treat AD 
June 28, 2019 
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3. Clinical diagnosis of dementia due to possible or probable AD consistent with criteria 
established by a workgroup of the National Institute on Aging and the Alzheimer's 
Disease Association. 
4. MMSE score ≥ 16 and ≤ 26 at screening, OR if > 26, a prior CSF total tau/Aβ42 ratio 
≥ 0.28. (A new CSF draw would be required for analysis of pre-dose biomarkers.) 
5. If female, postmenopausal for at least 1 year 
6. Patient living at home, senior residential setting, or an institutional setting without the 
need for continuous (i.e. 24-h) nursing care 
7. General health status acceptable for participation in the study 
8. Fluency (oral and written) in English or Spanish 
9. If receiving memantine, rivastigmine, galantamine or an AChEI, receiving a stable 
dose for at least 3 months (90 days) before screening and with continuous dosing for 
at least 3 months. If receiving donepezil, receiving any dose lower than 23 mg once 
daily. Multiple medications are allowed. 
10. The patient is a non-smoker for at least 3 years.  
11. The patient or legal representative must agree to comply with the drawing of blood 
samples for the PK assessments, laboratory assessments and PTI-125Dx, and with a 
lumbar puncture and the drawing of CSF samples for biomarker assessments. 
12. The patient has a ratio of total tau/Aβ42 in CSF that indicates AD. This value (total 
tau/Aβ42) will be ≥ 0.28. 
13. Patient has a caregiver or legal representative responsible for administering the drug 
and recording the time. 
5.3. EXCLUSION CRITERIA 
Patients meeting any of the following criteria will be excluded from the study: 
1. Exposure to an experimental drug, experimental biologic or experimental medical 
device within the longer of 5 half-lives or 3 months before screening 
2. Enrollment in the previous PTI-125 trial 
3. A medical condition that would interfere with a lumbar puncture  
4. Residence in a skilled nursing facility and requiring 24 h care. 
5. Clinically significant laboratory test results 

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6. Clinically significant untreated hypothyroidism (if treated, thyroid-stimulating 
hormone level and thyroid supplementation dose must be stable for at least 6 months 
before screening) 
7. Insufficiently controlled diabetes mellitus 
8. Renal insufficiency (serum creatinine > ULN) 
9. Malignant tumor within 3 years before screening (except squamous and basal cell 
carcinoma or cervical carcinoma in situ or localized prostate cancer or localized stage 
1 bladder cancer) 
10. History of ischemic colitis or ischemic enterocolitis 
11. Unstable medical condition that is clinically significant in the judgment of the 
investigator 
12. Alanine transaminase (ALT) or aspartate transaminase (AST) > ULN or total bilirubin 
> ULN.  
13. History of myocardial infarction or unstable angina within 6 months before screening 
14. History of more than 1 myocardial infarction within 5 years before screening 
15. Clinically significant cardiac arrhythmia (including atrial fibrillation), 
cardiomyopathy, or cardiac conduction defect (patients with a pacemaker are 
acceptable) 
16. Symptomatic hypotension, or uncontrolled hypertension  
17. Clinically significant abnormality on screening electrocardiogram (ECG), including 
but not necessarily limited to a confirmed QTc value ≥ 450 msec for males or ≥ 470 
msec for females.  
18. Stroke within 18 months before screening, or history of a stroke concomitant with 
onset of dementia 
19. History of brain tumor or other clinically significant space-occupying lesion on CT or 
MRI 
20. Head trauma with clinically significant loss of consciousness within 12 months before 
screening or concurrent with the onset of dementia 
21. Onset of dementia secondary to cardiac arrest, surgery with general anesthesia, or 
resuscitation 
22. Specific degenerative CNS disease diagnosis other than AD (eg, Huntington's disease, 
Creutzfeld-Jacob disease, Down's syndrome, Frontotemporal Dementia, Parkinson's 
disease) 
23. Wernicke's encephalopathy 

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24. Active acute or chronic CNS infection 
25. Donepezil 23 mg or greater QD currently or within 3 months prior to randomization 
26. Discontinued AChEI < 30 days prior to randomization 
27. Antipsychotics; low doses are allowed only if given for sleep disturbances, agitation 
and/or aggression, and only if the subject has received a stable dose for at least 3 
months before randomization 
28. Tricyclic antidepressants and monoamine oxidase inhibitors; all other antidepressants 
are allowed only if the subject has received a stable dose for at least 3 months before 
randomization 
29. Anxiolytics or sedative-hypnotics, including barbiturates (unless given in low doses 
for benign tremor); low doses of benzodiazepines and zolpidem are allowed only if 
given for insomnia/sleep disturbance, and only if the subject has received a stable 
dose for at least 3 months before randomization 
30. Immunosuppressants, including systemic corticosteroids, if taken in clinically 
immunosuppressive doses (Steroid use for allergy or other inflammation is 
permitted.) 
31. Antiepileptic medications if taken for control of seizures 
32. Chronic intake of opioid-containing analgesics 
33. Sedating H1 antihistamines 
34. Nicotine therapy (all dosage forms including a patch), varenicline (Chantix), or 
similar therapeutic agent within 30 days before screening 
35. Clinically significant illness within 30 days of enrollment  
36. History of significant neurological, hepatic, renal, endocrine, cardiovascular, 
gastrointestinal, pulmonary, or metabolic disease  
37. Positive serum hepatitis B surface antigen (HBsAg) or positive hepatitis C virus HCV 
antibody test at screening  
38. Positive HIV test at screening  
39. Positive urine drug test at screening 
40. Loss of a significant volume of blood (> 450 mL) within 4 weeks prior to the study 
41. Suicidality on C-SSRS at screening 

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6. STUDY DRUG 
6.1. PTI-125 PHYSICAL DESCRIPTION AND PREPARATION 
Investigational PTI-125 and matching placebo will be supplied by CSI as coated tablets 
in 20-count bottles.  
All remaining PTI-125 study drug will be returned to the sponsor or designee. 
6.1.1. Storage 
Bottles of PTI-125 tablets should be stored at controlled room temperature, 20-25º 
C (68-77º F)  and protected from light and moisture. 
 
6.1.2. Drug Accountability 
The Investigator will be responsible for monitoring the receipt, storage, dispensing 
and accounting of all study medications according to site SOPs. All invoices of 
study medication shipments must be retained in the site study file. Accurate, 
original site records must be maintained of drug inventory and dispensing. All 
records must be made available to the sponsor (or designee) and appropriate 
regulatory agencies upon request. 
6.2. ADMINISTRATION AND DOSING REGIMEN 
Patients will be randomized to receive placebo (20 patients) or 50 mg PTI-125 b.i.d. (20 
patients) or 100 mg PTI-125 b.i.d. (20 patients). Study drug should be taken 1-2 h 
before or after a meal. 
6.3. CONCOMITANT MEDICATIONS 
Use of prescription or non-prescription medications will be recorded during the 
study. Chronic medications must be stable for 3 months. 
7. STUDY PROCEDURES 
Appendix A presents the Schedule of Activities. 
Prior to any study-related activities, the Informed Consent Form must be signed and 
dated by the patient or legal representative and the caregiver. The format and content of 
the Informed Consent Form must be agreed upon by the Principal Investigator(s), the 
appropriate IRB and the Sponsor (or designee). The signed and dated Informed 
Consent Form must be retained by the Investigator in the subject's file. 

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7.1. LIVER CHEMISTRY STOPPING CRITERIA 
Liver chemistry threshold stopping criteria have been designed to assure patient safety 
and to evaluate liver event etiology during administration of Study Drug. 
Administration of Study Drug will be discontinued if any of the following liver 
chemistry stopping criteria occurs: 
 
• ALT or AST ≥ 2.5 x ULN.  
• ALT or AST ≥ 2 x ULN and total bilirubin ≥ 2 x ULN. Note: Serum bilirubin 
fractionation should be performed if total bilirubin is ≥ 2 x ULN. 
• ALT or AST ≥ 2 x ULN if associated with appearance or worsening of a rash 
or hepatitis symptoms (fatigue, nausea, vomiting, right upper quadrant pain or 
tenderness, fever, rash or eosinophilia).  
• ALP or GGT ≥ 2.5 x ULN. 
 
In the event of discontinuation due to liver abnormalities, the patient will be 
appropriately investigated to determine the potential cause. 
 
7.2. EVALUATIONS BY VISIT 
Follow-up visits can be scheduled +/- two (2) days from the actual Study Day number. Please 
notify Sponsor of changes so that the biomarker lab is aware of whole blood sample shipments. 
 
7.2.1. Screening Visit 1 (No longer than 30 days prior to Day 1) 
The following will be completed in the first screening visit: 
• Informed Consent.  
• Review of Inclusion and Exclusion Criteria 
• Medical history 
• Review of concomitant medications 
• MMSE evaluation 
• Columbia Suicide Severity Rating Scale (C-SSRS) 
• Physical examination, including measurement of vital signs (blood pressure, 
temperature, pulse and respiratory rate), height, weight  
• A 12-lead ECG (5-min supine) 
• Laboratory assessments, including serum chemistry, hematology, 
urinalysis, and screens for HCV, HIV and HBsAg. 
• Urine drug screen. 

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7.2.2. Screening Visit 2 (If all Screening Visit 1 criteria are met) 
• Cambridge Cognition testing (conducted prior to CSF collection) 
• CSF sample collection (5 mL)  
CSF total tau/Aβ42 criterion  (~1-week turnaround) must be met prior to Day 1. 
7.2.3. Study Day 1 (Dosing Initiation) 
Patients will come to the clinic in the morning. Prior to dosing, the following 
assessments will be conducted: 
• 
Confirmation of inclusion/exclusion criteria 
• Review of concomitant medications 
• Vital signs (blood pressure, temperature, pulse and respiratory rate). 
• Listen to heart and lungs 
• Cambridge Cognition testing; the average of this result and that of the 
second screening visit will be taken as the baseline value. 
• 
Blood sample collection for clinical laboratory tests 
• Blood sample collection for PTI-125Dx and mTOR assessments (8 mL 
total) 
• 
ECG 
Patients will be administered Study Drug at least 1 h before or after a meal. The 
patient will be discharged 2 h later with their supply of Study Drug.   
After dose on Study Day 1, the following assessments will be conducted: 
• Vital signs (blood pressure, temperature, pulse and respiratory rate) at 
approximately 30 min, and 1 and 2 h post-dose.  
• Adverse event monitoring 
Clinic personnel will monitor the patients for the occurrence of any adverse events 
until patients are discharged from the clinic. Upon investigator judgment, patients 
will be discharged from the clinic with their supply of study drug until the next visit. 
The caregiver will be instructed to administer study drug twice daily at least 1 h 
before or after a meal. A dose can be up to 4 h late, but if a dose is missed, the next 
dose should NOT be doubled.  
For all follow-up visits, patients will come to the clinic in the morning and will be instructed 
not to take their morning dose prior to coming to the clinic.  

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7.2.4. Day 7 Follow-up Visit 
Patients will return to clinic on Study Day 7 before taking their morning dose. 
On the morning of Study Day 7, within 30 min prior to dosing, the following 
assessments will be conducted: 
• 
Blood sample collection for PK assessment (for Cmin) 
• Clinical laboratory tests (blood and urine) 
After dose, the following will be conducted: 
• Vital signs (blood pressure, temperature, pulse and respiratory rate) 
• Listen to heart and lungs 
• Adverse event monitoring 
7.2.5. Day 14 Follow-up Visit 
Patients will return to clinic on Study Day 14 before taking their morning dose. 
On the morning of Study Day 14, within 30 min prior to dosing, the following 
assessments will be conducted: 
• 
Blood sample collection for PK assessment (for Cmin) 
• Clinical laboratory tests (blood and urine) 
After dose, the following will be conducted: 
• Vital signs (blood pressure, temperature, pulse and respiratory rate) 
• Listen to heart and lungs 
• Adverse event monitoring 
• ECG 
7.2.6. Day 28 Follow-up Visit 
Patients will return to the clinic in the morning on Study Day 28 and take their 
morning dose upon arrival. 
After dose on Study Day 28, the following assessments will be conducted: 
• Vital signs (blood pressure, temperature, pulse and respiratory rate)  
• Adverse event monitoring 

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• Cambridge Cognition testing 
• MMSE 
• Columbia Suicide Severity Rating Scale (C-SSRS) 
• ECG 
• CSF sample collection (time post-dose to be recorded) 
• 
Blood sample collection for PK (time post-dose to be recorded) 
• Clinical laboratory tests (blood and urine) 
• Blood sample collection for PTI-125Dx, mTOR and other biomarkers      
(8 mL total) 
CSF sample collection (5 mL) on Study Day 28 will occur 1-2 h after dosing and after 
the MMSE and Cambridge Cognition testing have been completed. These samples 
will be tested for PTI-125 levels as well as the Aβ/tau Index, YKL40, inflammatory 
cytokines and other biomarkers.  
 
Blood sample collection for PK assessment on Study Day 28 should be taken as soon 
after the CSF draw as possible to allow CSF to plasma ratio to be calculated. 
 
7.2.7. End-of-study Follow-up  
Patient will receive a follow-up phone call 7-14 days after the last dose. If needed, a 
follow-up clinic visit will be scheduled. 
 
7.2.8. Unscheduled Visits and Discontinuation due to AEs 
For unscheduled visits due to AEs, any assessments conducted will be at the 
discretion of the investigator and pertinent to the AE. If a decision is made to 
discontinue the patient from study drug, the Sponsor will be notified immediately. 
Restarting the patient on study drug will be a mutual decision by the investigator and 
the Sponsor. 
 
7.3. LABORATORY ASSESSMENTS 
7.3.1. Clinical Laboratory Tests 
The following clinical laboratory tests will be performed at screening, Day 1 pre-dose, 
and at follow-up visits on Day 7, 14, and 28: 
 
• Hematology:  white blood cell (WBC) count with differential, red blood 
cell (RBC) count, hemoglobin, hematocrit, platelet count. 

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• Serum Chemistry:  glucose, sodium, potassium, chloride, bicarbonate, 
calcium, phosphate, blood urea nitrogen (BUN), total bilirubin, 
creatinine, cholesterol, triglycerides, albumin, globulin, total protein, uric 
acid, alkaline phosphatase (ALP), alanine transaminase (ALT), aspartate 
transaminase (AST), gamma glutamyl transpeptidase (GGT), lactose 
dehydrogenase (LDH). 
• Urinalysis: color, specific gravity, pH, protein, glucose, ketones and 
occult blood. 
 
7.3.2. Preparation of Whole Blood Samples for biomarkers and APOE genotyping 
Blood samples to be assessed in blood-based (lymphocytes or plasma) biomarkers, 
e.g. PTI-125Dx and mTOR, or genotyping (8 mL total) will be drawn into a 
Vacutainer® tube containing K2EDTA. Collection will occur on Days 1 and 28. 
The tubes will be placed immediately on wet ice or in a refrigerator and shipped as 
whole blood, unfrozen, with cold gel packs (2-8°C) within 24 h to: Dr. Hoau-Yan 
Wang, CUNY School of Medicine, SOM CDI 3370, 85 St. Nicolas Terrace, New 
York, NY 10027. Do not freeze, do not ship with dry ice, and do not ship whole 
blood samples on Friday. 
7.3.3. Preparation of Plasma Samples for Pharmacokinetic Determination  
At each blood collection for PK, blood samples (4 mL) will be drawn into a 
Vacutainer® tube containing K2EDTA. The tubes will be placed on ice. Within 30 
min of collection, the blood will be centrifuged at approximately 1000 X G for 15 
min, preferably at 4-5°C. Within 30 min of centrifuging, plasma (at least 1.5 mL) 
will be split into two aliquots, transferred to polypropylene tubes and stored at 
approximately -20°C or below until analysis.  
At the end of the study or when advised by Sponsor, PK samples will be shipped 
frozen on dry ice to: Worldwide Clinical Trials Bioanalytical Sciences, 8609 Cross 
Park Drive, Austin, TX 78754 for bioanalytical analysis of PTI-125 with a validated 
assay. The second set of samples will be shipped separately once receipt of the first 
set is confirmed. One sample from each placebo subject will be analyzed. The 
timepoint will be selected to be near the Cmax.  
 
7.3.4. CSF assays 
CSF samples should be split, with 2.5 mL shipped to Dr. Wang at CUNY and, for 
Day 28 only, an additional 0.5 mL shipped to Worldwide Clinical Trials (WCT). This 
0.5 mL sample will be assayed for the PTI-125 analyte at WCT using a qualified 
assay.  The remaining 2.5 or 2 mL will be retained at the study site frozen at -20°C or 
below until informed by the Sponsor. 

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CSF will be collected into 5 ml Screw-Cap LoBind Eppendorf® tubes 
(# 0030122356). When dividing into aliquots, the same tubes can be used or a 2 ml 
Sarstedt® Screw Cap Micro Tube Protein Low Binding (#72.694.600). CSF 
samples will be collected at the second screening visit and on Study Day 28.   
The samples collected at screening and on Study Day 28 will be shipped frozen on 
dry ice (Monday – Wednesday) to Dr. Hoau-Yan Wang, CUNY School of Medicine, 
SOM CDI 3370, 85 St. Nicolas Terrace, New York, NY 10027 to be tested in 
biomarker assays including: 
• Abeta 
• Tau, ptau 
• YKL40 
• IL-6, TNFα and IL-1β 
• Neurogranin 
• Neurofilament light chain 
CSF samples collected at screening should be shipped to Dr. Wang upon collection; 
all Day 28 CSF samples can be held until end of study and shipped together per 
Sponsor instructions (2 mL samples), or for the 0.5 mL samples, to WCT along with 
plasma PK samples in one shipment. 
8. EARLY DISCONTINUATION 
Patients may choose to discontinue study drug or study participation at any time, for 
any reason, and without prejudice. Patients who discontinue may be replaced at the 
discretion of Sponsor. 
 
The following must be completed and documented in the source documents and CRFs 
for all patients who discontinue the study early: 
• 
The reason for early study discontinuation. 
• 
Vital signs (blood pressure, temperature, pulse and respiratory rate), full physical 
examination, clinical laboratory tests, ECG, use of concomitant medications, and 
adverse events) should be obtained at discharge prior to release. 
• 
Blood draw for PTI-125Dx, mTOR and other biomarkers 
• 
MMSE  
• 
Cambridge Cognition testing if not performed within the last 3 days 

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• 
CSF draw for biomarkers 
9. ADVERSE EVENTS/SERIOUS ADVERSE EVENTS  
9.1. ADVERSE EVENTS - DEFINITION 
An adverse event (AE) is any undesirable event that occurs to a subject during a 
study, whether or not that event is considered study drug-related. Monitoring for AEs 
will start at dosing. Examples include: 
• Any treatment-emergent signs and symptoms (events that are marked by a change 
from the subject's baseline/entry status [e.g., an increase in severity or frequency 
of pre-existing abnormality or disorder]) 
• All reactions from study drug, an overdose, abuse of drug, withdrawal 
phenomena, sensitivity or toxicity to study drug 
• Apparently unrelated illnesses 
• Injury or accidents (Note: if a medical condition is known to have caused the 
injury or accident, the medical condition and the accident should be reported as 
two separate medical events [e.g., for a fall secondary to dizziness, both 
"dizziness" and "fall" should be recorded separately]) 
• Extensions or exacerbations of symptoms, subjective subject-reported events, 
new clinically significant abnormalities in clinical laboratory, physiological 
testing or physical examination 
 
All AEs, whether or not related to the study drug, must be fully and completely 
documented on the AE page of the CRF and in the subject's clinical chart. 
In the event that a subject is withdrawn from the study because of an AE, it must be 
recorded on the CRF as such. The subject should be followed and treated by the 
Investigator until the abnormal parameter or symptom has resolved or stabilized. 
The Investigator must report all directly observed AEs and all spontaneously reported 
AEs. The Investigator will ask the subject a non-specific question (e.g., "Have you 
noticed anything different since your dose of the study medication?") to assess 
whether any AEs have been experienced since the last assessment. AEs will be 
identified and documented on the AE CRF in appropriate medical terminology. The 
severity and the relationship to the study drug will be determined and reported on the 
CRF (see below). 

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9.2. ADVERSE EVENTS - SEVERITY RATING 
The severity of each AE should be characterized and then classified into one of three 
clearly defined categories as follows: 
• Mild - the AE does not interfere in a significant manner with the subject's 
normal functioning level. It may be an annoyance. 
• Moderate - the AE produces some impairment of functioning but is not 
hazardous to health. It is uncomfortable or an embarrassment. 
• Severe - the AE produces significant impairment 
of functioning or 
incapacitation and is a definite hazard to the subject's health. 
These three categories are based on the Investigator's clinical judgment, which in turn 
depends on consideration of various factors such as the subject's report, and the 
physician's observations. The severity of the AE should be recorded in the appropriate 
section of the Adverse Event CRF. 
9.3. ADVERSE  EVENTS  -  RELATIONSHIP TO  STUDY DRUG 
The relationship of each AE to the study drug will be classified into one of three 
defined categories as follows: 
• Unlikely - a causal relationship between the AE and the study drug is unlikely. 
• Possible - a causal relationship between the AE and the study drug is possible. 
• Probable - a causal relationship between the AE and the study drug is probable. 
For example, the AE is a common adverse event known to occur with the 
pharmacological class the study drug belongs to; or the AE abated on study 
drug discontinuation and reappeared upon rechallenge with the study drug. 
These three categories are based on the Investigator's clinical judgment, which in turn 
depends on consideration of various factors such as the subject's report, the timing of 
the AE in relationship to study drug administration/discontinuation, the physician's 
observations and the physician's prior experience. The relationship of the AE to the 
study drug will be recorded in the appropriate section of the Adverse Event eCRF. 
9.4. SERIOUS ADVERSE EVENTS AND UNEXPECTED ADVERSE EVENTS - DEFINITIONS 
A Serious Adverse Event (SAE) includes (but is not limited to) an experience 
occurring at any dose that results in any of the following outcomes: 
• Death 
• A life-threatening event (i.e., the subject is at immediate risk of death from the 
reaction as it occurs). "Life-threatening" does not include an event that, had it 

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occurred in a more serious form, might have caused death. For example, drug- 
induced hepatitis that resolved without evidence of hepatic failure would not be 
considered life-threatening even though drug-induced hepatitis can be fatal. 
• In-patient hospitalization (hospital admission, not an emergency room visit) or 
prolongation of existing hospitalization. 
• A persistent or significant disability/incapacity (i.e., a substantial disruption of 
the subject's ability to carry out normal life functions). 
• A congenital anomaly/birth defect. 
 
In addition, medical and scientific judgment should be exercised in deciding whether 
other situations should be considered an SAE (i.e., important medical events that may 
not be immediately life-threatening or result in death but may jeopardize the subject 
or may require medical or surgical intervention to prevent one of the other outcomes 
listed in the definition above). Examples of such medical events include (but are not 
limited to): allergic bronchospasm requiring intensive treatment in an emergency 
room or at home, blood dyscrasias or convulsions that do not result in in-patient 
hospitalization, or the development of drug dependency or drug abuse. 
An unexpected AE is one for which the specificity or severity is not consistent with 
the current Investigator's Brochure. For example, hepatic necrosis would be 
unexpected (by virtue of greater severity) if the Investigator's Brochure only listed 
elevated hepatic enzymes or hepatitis. 
Similarly, cerebral thromboembolism and cerebral vasculitis would be unexpected (by 
virtue of greater specificity) if the Investigator's Brochure only listed cerebral 
vascular accidents. 
9.5. SERIOUS ADVERSE EVENTS REPORTING 
The reporting of SAEs by the Sponsor to Regulatory Authorities (e.g., FDA) is a 
regulatory requirement. Each Regulatory Agency has established a timetable for 
reporting SAEs based upon established criteria.  Likewise, it is the responsibility of 
the Principal Investigator to report SAEs to their EC/IRB. 
 
All SAEs must be reported immediately (within 24 h of learning of the event) by 
telephone to: 
 
Nadav Friedmann, PhD, MD 
Cassava Sciences, Inc. 
Email: nfriedmann@cassavasciences.com 
Phone:    925-788-4585 

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Do not delay reporting a suspected SAE to obtain additional information.  Any 
additional information, if collected, can be reported to the Sponsor as a follow-up 
to the initial report. 
A completed SAE report form must be faxed within five working days to the 
medical monitor. SAEs must also be reported to the responsible EC/IRB 
immediately. 
In the case of a death or other SAE that has occurred within 30 days after 
receiving study drug, the Principal Investigator must also report such an event 
within 24 hours of being notified. Your local EC/IRB may also require these 
reports. 
In the event of any SAE (other than death), the subject will be instructed to 
contact the study physician (Principal Investigator or designee) using the phone 
number provided in the Informed Consent Form. All patients experiencing an 
SAE will be seen by a Principal Investigator or designee as soon as feasible 
following the report of an SAE. 
10. STATISTICAL CONSIDERATIONS 
10.1. RANDOMIZATION 
Randomized treatments will be assigned by patient numbers in a randomly generated 
numeric sequence. 
The randomization code will not be revealed to study patients, investigators, clinical 
staff or study monitors until all patients have completed therapy and the database has 
been finalized and locked.  
Under normal circumstances, the blind should not be broken. The blind may be broken 
only if specific emergency treatment is indicated. The date, time and reason for the 
unblinding must be documented on the case report form, and the medical monitor must 
be informed as soon as possible. 
10.2. ANALYSIS POPULATIONS 
All patients who receive study medication will be included in analyses for safety, 
biomarkers and cognition.  
10.3. PHARMACOKINETIC PARAMETERS 
The only plasma PK parameters to be collected from this study are the Cmin values from 
blood samples taken prior to dosing on Days 7 and 14 and the sample on Day 28 

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collected just after the CSF draw. 
 
A CSF to plasma ratio will be determined using the Day 28 CSF and plasma samples. 
10.4. STATISTICAL ANALYSIS 
CSF biomarker endpoints to be analyzed include: 1) neurogranin, 2) neurofilament light 
chain, 3) total tau, 4) pTau (T181), 5) Aβ42, 6) YKL40, 7) IL-6, 8) TNFα, and 9) IL-1β. 
Plasma and lymphocyte assays include 1) PTI-125Dx lymphocyte assay, 2) PTI-125Dx 
plasma assay and 3) mTOR assay. CSF biomarkers may also be measured in plasma. 
All biomarker data will be analyzed by a two-tailed paired t test or other appropriate 
statistics. 
 
Although not powered for efficacy, the Cambridge Cognition tests will be analyzed by 
repeated measures ANOVA or other appropriate statistics. 
 
10.5. SAFETY ANALYSIS 
Adverse events reported on case report forms will be mapped to preferred terms and 
organ systems using the MedDRA mapping system. Vital signs and clinical 
laboratory results will be descriptively summarized in terms of change from 
screening values. 
10.6. SAMPLE SIZE 
Sixty (60) patients will be enrolled in this study. Sample size was determined by 
estimating the intrasubject variability for log-transformed data from previous studies 
of new chemical entities (NCEs). 
11. STUDY TERMINATION 
The study will be terminated following completion of the study or at any time at the 
discretion of the Sponsor. 
12. DATA COLLECTION, RETENTION AND MONITORING 
12.1. CASE REPORT FORMS 
Electronic case report forms (eCRFs) will be used for each subject. The patients in 
the study will not be identified by name on any study documents to be collected by 
the Sponsor (or CRO designee) but will be identified by a unique patient number. 

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All clinical information requested in this protocol will be recorded in the eCRFs 
provided by CSI.  Case report forms must be completed within 48 hours of a patient’s 
visit. In case of error, the correction will be noted, initialed and dated. 
eCRFs must be reviewed and verified for accuracy and signed-off by the Principal 
Investigator before collection by the Sponsor (or CRO designee). Paper source 
documents, if used, will remain at the Investigator's site at the completion of the 
study. 
12.2. AVAILABILITY AND RETENTION OF INVESTIGATIONAL RECORDS 
The Investigator must make study data accessible to the monitor, other authorized 
representatives of the Sponsor (or designee) and Regulatory Agency (e.g., FDA) 
inspectors upon request. To assure accuracy of data collected in the eCRFs, it is 
mandatory that Sponsor representatives have access to original source documents 
(e.g., subject records, subject charts, and laboratory reports). During review of these 
documents, the subject's anonymity will be maintained with adherence to 
professional standards of confidentiality and applicable laws. A file for each subject 
must be maintained that includes the signed Informed Consent Form and all source 
documentation related to that subject. The Investigator must ensure the reliability and 
availability of source documents for the eCRF. 
Investigators are required to maintain all study documentation until notification by 
CSI that any records may be discarded. 
The Investigator is responsible for maintaining adequate case histories in each 
subject's source records.  
12.3. SUBJECT CONFIDENTIALITY 
All reports and subject samples will be identified only by the assigned patient number 
and initials to maintain subject confidentiality. Additional subject confidentiality 
issues (if applicable) are covered in the Clinical Trial Agreement. 
12.4. LIABILITY 
In the event of a side effect or injury, appropriate medical care as determined by the 
Investigator or his/her designated alternate will be provided. 
If a bodily injury is sustained, resulting directly from the use of the study drug, the 
Sponsor will reimburse for reasonable physician fees and medical expenses 
necessary for treatment of only the bodily injury which is not covered by the 
subject's medical or hospital insurance, provided that the injury is not due to a 
negligent or wrongful act or omission by the study doctor and his/her staff. No other 

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compensation of any type will be provided by the Sponsor. Compensation for lost 
wages, disability or discomfort due to the study is not available. 
12.5. ETHICAL AND LEGAL ISSUES 
The Investigator and site personnel are responsible for conducting this study in 
accordance with the ICH, GCP, and all other applicable laws and regulations. 
12.5.1. Institutional Review Board 
The protocol and Informed Consent Form must be approved by an IRB before the 
study is initiated. The IRB must comply with U.S. CFR 21 Part 56 and local laws. 
Documentation of IRB approval must be provided to the Sponsor. Investigators are 
responsible for the following: 
• Obtaining IRB approval of the protocol, Informed Consent Form, and any 
advertisements to recruit patients and IRB approval of any protocol 
amendments and Informed Consent Form revisions before implementing the 
changes. 
• Providing the IRB with any required information before or during the study. 
• Submitting progress reports to the IRB, as required, requesting additional 
review and approval, as needed; and providing copies of all relevant IRB 
communications to the Sponsor. 
• Notifying the IRB within 15 calendar days of all SAEs and unexpected AEs 
related to study medications reported by the Sponsor to the Investigator. 
12.6. INFORMED CONSENT FORM 
The Sponsor (or designee) must review the Investigator's proposed Informed Consent 
Form prior to IRB submission for approval. An IRB-approved copy of the Informed 
Consent Form will be forwarded to the Sponsor. 
The Informed Consent Form documents study-specific information the Investigator 
provides to the subject and the subject's agreement to participate. The Investigator 
explains in plain terms the nature of the study along with the aims, methods, 
anticipated benefits, potential risks, and any discomfort that participation may entail. 
The Informed Consent Form must be signed and dated before the subject enters the 
study. The original Informed Consent Form and any amended Informed Consent 
Form, signed and dated, must be retained in the subject's file at the study site and a 
copy must be given to the subject. 

Cassava Sciences, Inc. 
Clinical Protocol PTI-125-02 
PTI-125, a small molecule to treat AD 
June 28, 2019 
Page 31 of 33 
 
 
 
 
CONFIDENTIAL 
13.  INVESTIGATOR RESPONSIBILITIES 
The Investigator agrees to: 
• Conduct the study in accordance with the protocol, except to protect the safety, 
rights, or welfare of patients. 
• Personally conduct or supervise the study. 
• Ensure that requirements for obtaining informed consent and EC/IRB review 
and approval comply with ICH, CFR 21 Parts 50 and 56 and local laws. 
• Report to the Sponsor any AEs that occur during the study in accordance with 
ICH, CFR 21 Part 312.64 and local laws. 
• Read and understand the Investigator's Brochure including potential risks and 
side effects of the drug. 
• Ensure that all associates, colleagues, and employees assisting in the conduct of 
the study are informed about their obligations in meeting the above 
commitments. 
• Maintain adequate records in accordance with ICH, 21 CFR Part 312.62, and 
local laws and have records available for inspection by the Sponsor, FDA, or 
other authorized agency. 
• Ensure that EC/IRB complies with requirements of ICH, 21 CFR Part 56, and 
local laws and will be responsible for initial and continuing review and approval 
of the clinical study. 
• Promptly report to the EC/IRB and the Sponsor all changes in research activity and 
unanticipated problems involving risks to patients or others (including 
amendments and expedited safety reports). 
• Comply with all other requirements regarding obligations of Clinical 
Investigators and all other pertinent requirements listed in ICH, 21 CFR Part 
312 and local laws. 

Cassava Sciences, Inc. 
Clinical Protocol PTI-125-02 
PTI-125, a small molecule to treat AD 
June 28, 2019 
Page 32 of 33 
 
 
 
 
CONFIDENTIAL 
 
14. REFERENCES 
1. 
Burns LH, Wang H-Y. Altered filamin A enables amyloid beta-induced tau 
hyperphosphorylation and neuroinflammation in Alzheimer’s disease. Neuroimmunol 
Neuroinflammation 2017;4:263-71. 
 
2. 
Wang H-Y, Lee K-C, Pei Z, Khan A, Bakshi K, Burns L. PTI-125 binds and reverses an 
altered conformation of filamin A to reduce Alzheimer's disease pathogenesis. 
Neurobiol Aging 2017;55:99-114. 
 
3. 
Wang H-Y, Bakshi K, Frankfurt M, et al. Reducing amyloid-related Alzheimer’s 
disease pathogenesis by a small molecule targeting filamin A. J Neurosci 
2012;32:9773-84. 

Cassava Sciences, Inc. 
Clinical Protocol PTI-125-02 
PTI-125, a small molecule to treat AD 
June 28, 2019 
Page 33 of 33 
 
 
 
 
CONFIDENTIAL 
 
15.  APPENDIX A – SCHEDULE OF ACTIVITIES 
 
PROCEDURE 
SCREEN 1  
(Days -29 to 
Day -1) 
SCREEN 2  
(Days -28 
to Day 0) 
DAY 1 
Time=0 
DAY  
7 
DAY 
14 
DAY 
28 
Informed consent 
X 
 
 
 
 
 
Medical and medication 
histories 
X 
 
X 
 
 
 
ECG  
X 
 
X 
 
X 
X 
Vital signs 
X 
 
X 
X 
X 
X 
Physical examination 
X 
 
* 
* 
* 
X 
FSH Test** 
X 
 
 
 
 
 
Biochemistry, hematology, 
urinalysis 
X 
 
X 
X 
X 
X 
MMSE  
X 
 
 
 
 
X 
HCV, HBsAg & HIV screen 
X 
 
 
 
 
 
Urine drug screen 
X 
 
 
 
 
 
Drug administration 
 
 
X 
X 
X 
X 
Blood sample collection for 
PK analysis 
 
 
 
X 
X 
X 
Adverse Events 
 
 
X 
X 
X 
X 
Blood draw for biomarkers 
and one time only, APOE 
genotyping 
 
 
X 
 
 
X 
Cambridge Cognition testing 
 
X 
X 
 
 
X 
C-SSRS 
X 
 
 
 
 
X 
CSF draw 
 
X 
 
 
 
X 
* Listen to heart and lungs      ** If female and last natural menses < 24 months or uncertain