Clinical trial NCT04388254
Conditions: Alzheimer Disease
Sponsor: Cassava Sciences, Inc.
Start date: 2020-03-24; Completion date: 2023-11-09
Enrollment: 220 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
A two-year safety study of simufilam (PTI-125) 100 mg oral tablets twice daily for participants of the previous simufilam studies as wells as additional new mild-to-moderate Alzheimer's disease subjects for a total of 200 participants. All participants will receive simufilam 100 mg tablets twice daily for one year, followed by a 6-month randomized, double-blind period where subjects will either continue on active treatment or be switched to placebo. The study concludes with an additional 6-month open-label treatment period. Clinic visits are every month or month and a half in the first year, and every 3 months in the second year with an additional visit at Month 13. Cognition and neuropsychiatric symptoms are evaluated.

Detailed description:
The objectives of this study are to build the safety database for simufilam (PTI-125) and to investigate its effects on biomarkers, cognition and neuropsychiatric symptoms during 12-month twice-daily administration in mild-to-moderate AD patients. Additional objectives are to assess differences in cognition and neuropsychiatric symptoms between active and placebo arms in the 6-month randomized period. All subjects will undergo lumbar puncture at screening for baseline testing of cerebrospinal fluid (CSF) total tau and Abeta42, and the first 50 subjects will also provide a CSF sample at Month 6 or Month 12 for evaluation of change from baseline in CSF biomarkers. CSF will not be required of subjects with prior CSF, PET or MRI evidence of Alzheimer's disease. Plasma biomarkers will be evaluated in all subjects. Safety will be assessed by blood tests, electrocardiograms, adverse event monitoring and, at Months 12 and 24, full physical examinations.

Arms: arm 1: Simufilam 100 mg oral tablets administered twice daily (BID) for the full 24 months (including the randomized period Month 12 to Month 18) arm 2: This placebo arm is only for Month 12 to Month 18. Day 1 to Month 12, as well as Month 18 to Month 24 are open-label treatment periods of simufilam 100 mg b.i.d. for all subjects.
Interventions: intervention 1: Simufilam 100 mg oral tablet intervention 2: Placebo
Intervention descriptions: intervention 1: Simufilam 100 mg oral tablet for b.i.d. administration intervention 2: Matching placebo oral tablets

Protocol documents:
SAP_002.pdf: 
Statistical Analysis Plan 
PTI-125-04 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
A 12-Month, Open-Label Safety Study of Simufilam followed by a 6-Month 
Randomized Withdrawal and 6 Additional Months Open- Label in Mild-to-
moderate Alzheimer’s Disease Patients 
NCT #: 04388254 
v3.0 December 8, 2023 
 
Statistical Analysis Plan for Final Analysis 
PTI-125-04 
 
 
 







































Prot_000.pdf: 
 
Cassava Sciences, Inc. 
Clinical Protocol PTI-125-04 
Simufilam (PTI-125), A small molecule to treat AD 
June 11, 2021 
 
Amendment #7 
 
 
Page 1 of 39 
 
 
 
 
CONFIDENTIAL  
 
7801 N. Capital of Texas Hwy, Ste. 260 
Austin, TX 78731 
CLINICAL RESEARCH PROTOCOL 
PROTOCOL PTl-125-04 
 
A 12-Month, Open-Label Safety Study of Simufilam followed by a 
6-Month Randomized Withdrawal and 6 Additional Months 
Open-Label in Mild-to-moderate Alzheimer’s Disease Patients 
 
Sponsor:  
 
 
 
Cassava Sciences, Inc. 
7801 N. Capital of Texas Hwy, Ste. 260 
Austin, TX 78731 
 
Program Lead:  
Lindsay H. Burns, PhD 
 
SVP, Neuroscience 
 
Phone:     512-501-2484 
 
Email:      lburns@cassavasciences.com 
 
Study Monitor: 
Nadav Friedmann, PhD, MD 
Chief Operating & Medical Officer  
Phone: 925-788-4585 
Email: 
nfriedmann@cassavasciences.com 
 
Project Manager 
Ben J. Murray 
 
Sr. Clinical Project Manager  
 
Phone:    512-501-3180 
 
Email:     bmurray@cassavasciences.com 
 
Protocol Date: 
February 10, 2020 
Amendment #1 
March 17, 2020 
Amendment #2 
April 02, 2020 
Amendment #3 
May 6, 2020 
Amendment #4 
October 28, 2020 
Amendment #5 
December 30, 2020 
Amendment #6 
Feb 8, 2021 
Amendment #7 
June 11, 2021 
 
This clinical trial is supported by NIH grant AG065152.  
Confidentiality: The information contained in this document and all information 
provided to you related to simufilam ("Study Drug") are the confidential and proprietary 
information of Cassava Sciences 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 
Cassava. 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-125-04 
Simufilam (PTI-125), A small molecule to treat AD 
June 11, 2021 
 
Amendment #7 
 
 
Page 2 of 39 
 
 
 
 
CONFIDENTIAL  
 
SUMMARY OF PROTOCOL AMENDMENT #7 
 
Approvals: 
Changed:   Carrie Crowley  
 
 
 
 
Director, Quality 
Assurance 
Changed to:   Ben J. Murray 
 
 
 
 
 
Sr. Clinical Project 
Manager 
Changed throughout where vital signs are listed: 
• Vital signs (blood pressure, temperature, pulse and respiratory rate) 
Changed to:  
• Vital signs (blood pressure, temperature, pulse and respiratory rate), and weight 
 
4. SUMMARY OF STUDY DESIGN 
 
Changed: approximately 150 patients 
Changed to: up to 200 patients 
Added to list of Day 1 activities: and the C-SSRS. 
Changed: PK blood samples will be obtained in the morning before dosing at all 
return visits except Months 4.5, 7.5 and 10.5.  
Changed to: PK blood samples will be obtained in the morning before dosing at 
return visits on Months 15 and 18.  
5.1 STUDY POPULATION 
Changed: Between 100 and 150 patients will be enrolled 
Changed to: Up to 200 patients will be enrolled 
5.3 Exclusion Criteria 
Changed 29, 30, 31, 32, 33: Prior to randomization 
Changed to: Prior to enrollment 
Changed 41: Loss of significant volume of blood (>450 mL) within 4 weeks prior to 
the study 


 
Cassava Sciences, Inc. 
Clinical Protocol PTI-125-04 
Simufilam (PTI-125), A small molecule to treat AD 
June 11, 2021 
 
Amendment #7 
 
 
Page 3 of 39 
 
 
 
 
CONFIDENTIAL  
Changed to: Loss of significant volume of blood (>450 mL) within 4 weeks prior to 
enrollment 
Changed 42: COVID-19 infection within 3 months 
Changed to: COVID-19 infection within 3 months of screening 
7.2.1 Screening Visit 1 (days -29 to 0) 
Added:   Confirmation that the patient is either fully vaccinated for the COVID-19 
virus at least 2 weeks prior to first dose of simufilam, or a positive serology test for the 
COVID-19 virus with no current symptoms 
7.2.4 Follow-up Visits on Months 1, 3, and 9, 13, 15 and 21 
 
Changed: Within 30 min prior to dosing, the following assessments will be 
conducted: 
• 
Blood sample collection for PK assessment (for Cmin) 
Changed to: Within 30 min prior to dosing, the following assessments will be 
conducted: 
• 
Blood sample collection for PK assessment (for Cmin – Month 15 only) 
Changed: Cheek swab for genetic testing Month 15 Visit only 
Changed to: Saliva collection for genetic testing Month 15 Visit only 
7.2.5 Follow-up Visit on Month 2 
Deleted: Blood sample collection for PK assessment (for Cmin) 
 
7.2.6 Follow-up Visits on Months 4.5, 7.5, and 10.5 
Changed:  Patients will return to clinic at any time of day 
Changed to:  Patients will return to clinic at any time of day. The visit may be 
conducted by telemedicine, based on the judgement of the Investigator 
 
7.2.7 Follow-up Visit on Month 6 and 18 
Changed: Blood sample collection for PK assessment (for Cmin) 
Changed to:  Blood sample collection for PK assessment (for Cmin – Month 18 
only) 


 
Cassava Sciences, Inc. 
Clinical Protocol PTI-125-04 
Simufilam (PTI-125), A small molecule to treat AD 
June 11, 2021 
 
Amendment #7 
 
 
Page 4 of 39 
 
 
 
 
CONFIDENTIAL  
Moved from After Dose to Within 30 min prior to dosing: Plasma sample collection (from 
8 mL whole blood) for SavaDx and other plasma biomarkers. 
7.2.8 Follow-up Visit on Month 12 and 24 
Added for clarity: Month 12 morning dose in the clinic will be from Open-Label 
Period 1 bottle.  Month 12 evening dose will be from the Randomized Period 2 bottle. 
Deleted: Blood sample collection for PK assessment (for Cmin) 
Moved from After Dose to Within 30 min prior to dosing: Plasma sample collection (from 
8 mL whole blood) for SavaDx and other plasma biomarkers. 
7.3.2 Preparation of Plasma Samples for Lymphocyte and Plasma Biomarker Determination 
Added: These patients with prior samples shipped as whole blood will continue to 
have samples shipped as whole blood only through Month 12. Samples at Months 
15, 18, 21 and 24 will be spun to plasma. 
7.3.3 Preparation of Plasma Samples for Pharmacokinetic Determination 
Changed: At each blood collection for PK (pre-dose samples for Cmin at all visits 
except Months 4.5, 7.5 and 10.5),  
Changed to: At each blood collection for PK (pre-dose samples for Cmin at Months 15  
and 18 only),  
7.3.5 Collection of Cheek Swab Saliva Samples for Genetic Testing 
Entire section changed from: Cheek swab saliva samples will be collected only at 
Month 15. Patients will refrain from eating or drinking 1 h prior to saliva collection. 
Each patient will be instructed to place a standard 2" × 2" piece of cotton gauze in the 
buccal region of their cheek for 3 min. The saliva-saturated cotton spit wad will be 
removed, rolled to fit a collection tube, and stored at -20°C until instructed to ship by 
the Sponsor. 
Changed to: Saliva samples will be collected only at Month 15. Patients will refrain 
from eating or drinking 1 h prior to saliva collection. Each patient will be instructed to 
spit into a saliva collection tube. The saliva will be stored at -20°C until instructed to 
ship by the Sponsor. 
8. EARLY DISCONTINUATION 
Changed: Patients who discontinue will not be replaced. 
Changed to: Patients who discontinue may be replaced at Sponsor discretion. 


 
Cassava Sciences, Inc. 
Clinical Protocol PTI-125-04 
Simufilam (PTI-125), A small molecule to treat AD 
June 11, 2021 
 
Amendment #7 
 
 
Page 5 of 39 
 
 
 
 
CONFIDENTIAL  
9.5 SERIOUS ADVERSE EVENTS REPORTING 
Added: or notification via email through the EDC system 
10.2 PHARMACOKINETIC ANALYSIS 
Changed: The only plasma PK parameters to be collected from this study are the Cmin 
values from blood samples taken prior to dosing on Months 1, 2, 3 and 9, as well as the 
sample on Month 6 or 12 collected just after the CSF draw (taken only if undergoing a 
CSF draw). 
Changed to: The only plasma PK parameters to be collected from this study are the 
Cmin values from blood samples taken prior to dosing at Months 15 and 18. 
10.5 PHARMACOKINETIC ANALYSIS 
Changed: Between 100 and 150 patients 
Changed to: Up to 200 patients 
15. APPENDIX A  
 
Event schedule has been updated to reflect PK samples taken only at 
Months 15 and 18 and addition of weight when vital signs are taken. 
Modified footnote “a” to state patients should be reconsented at their 
next study visit.  Additionally, a notation is made to omit drug 
dispensation at Month 24. 




 
Cassava Sciences, Inc. 
Clinical Protocol PTI-125-04 
Simufilam (PTI-125), A small molecule to treat AD 
June 11, 2021 
 
Amendment #7 
 
 
Page 7 of 39 
 
 
 
 
CONFIDENTIAL  
 
Cassava Sciences, Inc. 
CLINICAL RESEARCH PROTOCOL 
 
 
 
 
A 12-Month, Open-Label Safety Study of Simufilam followed by 
a 6-Month Randomized Withdrawal and 6 Additional Months 
Open-Label in Mild-to-moderate Alzheimer’s Disease Patients  
 
 
 
Signature of Agreement for Protocol PTI-125-04 
Amendment #7 
 
 
 
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-125-04 
Simufilam (PTI-125), A small molecule to treat AD 
June 11, 2021 
Amendment #7 
 
 
Page 8 of 39 
 
 
 
 
CONFIDENTIAL  
TABLE OF CONTENTS 
1. 
List of abbreviations ............................................................................................... 10 
2. 
INTRODUCTION .................................................................................................. 12 
2.1. Mechanism of Action ..................................................................................................... 12 
2.2. Safety pharmacology and toxicology ............................................................................... 12 
2.3. Clinical Studies ............................................................................................................. 13 
2.3.1. A first-in-human Single Ascending Dose clinical trial ........................................ 13 
2.3.2. First-in-patient multidose linical trial in mild-to-moderate AD patients ............... 13 
2.3.3. Double-blind placebo-controlled clinical trial in mild-to-moderate AD patients.. 14 
2.3.4. Open-label safety clinical trial in mild-to-moderate AD patients ........................ 15 
3. 
STUDY OBJECTIVES ............................................................................................. 16 
4. 
SUMMARY OF STUDY DESIGN .......................................................................... 16 
5. 
SUBJECT SELECTION ........................................................................................... 17 
5.1. Study Population ........................................................................................................... 17 
5.2. Inclusion Criteria ........................................................................................................... 17 
5.3. Exclusion Criteria .......................................................................................................... 18 
6. 
STUDY DRUG ...................................................................................................... 20 
6.1. Study Drug Physical Description and Preparation ............................................................. 20 
6.1.1. Storage .............................................................................................................. 21 
6.1.2. Drug Accountability ............................................................................................ 21 
6.2. Administration and Dosing Regimen ............................................................................. 21 
6.3. Concomitant Medications ................................................................................................ 21 
7. 
STUDY PROCEDURES........................................................................................... 21 
7.1. stopping criteria ............................................................................................................. 21 
7.2. Evaluations by Visit ....................................................................................................... 22 
7.2.1. Screening Visit 1 (Days -29 to 0) ....................................................................... 22 
7.2.2. Screening Visit 2 (Days -28 to 0) ........................................................................ 23 
7.2.3. Study Day 1  (Dosing Initiation) ......................................................................... 23 
7.2.4. Follow-up Visits on Months 1, 3, 9, 13, 15, 21 ................................................... 24 
7.2.5. Follow-up Visit on Month 2 ................................................................................ 24 
7.2.6. Follow-up Visits on Months 4.5, 7.5 and 10.5 .................................................... 25 
7.2.7. Follow-up Visits on Month 6 and 18 ................................................................... 25 
7.2.8. Month 12 and 24 Follow-up Visits ...................................................................... 26 
7.2.9. Withdrawal Day 1 Visit – If Needed ................................................................... 27 
7.3. Laboratory Assessments ................................................................................................. 27 


 
Cassava Sciences, Inc. 
Clinical Protocol PTI-125-04 
Simufilam (PTI-125), A small molecule to treat AD 
June 11, 2021 
Amendment #7 
 
 
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CONFIDENTIAL  
7.3.1. Clinical Laboratory Tests .................................................................................... 27 
7.3.2. Preparation of Whole Blood Samples for Lymphocyte and Plasma Biomarkers 28 
7.3.3. Preparation of Plasma Samples for Pharmacokinetic Determination .................. 28 
7.3.4. Preparation of CSF samples .............................................................................. 28 
7.3.5. Collection of Cheek Swab Saliva Samples for Genetic Testing ........................ 28 
8. 
EARLY DISCONTINUATION ................................................................................. 29 
9. 
ADVERSE EVENTS/SERIOUS ADVERSE EVENTS ................................................. 29 
9.1. Adverse Events - Definition ............................................................................................ 29 
9.2. Adverse Events - Severity Rating .................................................................................... 30 
9.3. Adverse  Events  -  Relationship to  Study  Drug ............................................................... 30 
9.4. Serious Adverse Events and Unexpected Adverse Events - Definitions .............................. 31 
9.5. Serious Adverse Events Reporting .................................................................................. 32 
10. 
STATISTICAL CONSIDERATIONS ......................................................................... 32 
10.1. Analysis Populations ...................................................................................................... 32 
10.2. Pharmacokinetic Parameters ........................................................................................... 33 
10.3. Statistical Analysis ........................................................................................................ 33 
10.4. Safety Analysis .............................................................................................................. 33 
10.5. Sample Size .................................................................................................................. 33 
11. 
STUDY TERMINATION ......................................................................................... 33 
12. 
DATA COLLECTION, RETENTION AND MONITORING ....................................... 34 
12.1. Case Report Forms ......................................................................................................... 34 
12.2. Availability and Retention of Investigational Records ....................................................... 34 
12.3. Subject Confidentiality ................................................................................................... 34 
12.4. Liability ........................................................................................................................ 35 
12.5. Ethical and Legal Issues ................................................................................................. 35 
12.5.1. Institutional Review Board .................................................................................. 35 
12.6. Informed Consent Form ................................................................................................. 36 
13. 
INVESTIGATOR RESPONSIBILITIES ................................................................... 36 
14. 
REFERENCES ...................................................................................................... 37 
15. 
Appendix A ........................................................................................................... 38 
 


Cassava Sciences, Inc. 
Clinical Protocol PTI-125-04 
Simufilam (PTI-125), A small molecule to treat AD 
June 11, 2021 
Amendment #7 
 
 
 
Page 10 of 39 
 
 
CONFIDENTIAL 
1. LIST OF ABBREVIATIONS 
7nAChR  
 
 
7 nicotinic acetylcholine receptor 
A42 
 
 
 
amyloid beta1-42 
AChEI  
 
 
acetylcholinesterase inhibitor 
AD 
 
 
 
Alzheimer’s disease 
ADAS-Cog11  
 
Alzheimer’s Disease Assessment Scale cognitive subscale 11 
ADME 
 
 
absorption, distribution, metabolism, excretion 
ANDI  
 
 
Alzheimer’s Disease Neuroimaging Initiative 
AE 
 
 
 
adverse event 
ALP 
 
 
 
alkaline phosphatase 
ALT   
 
 
alanine transaminase 
ANOVA 
 
 
analysis of variance 
AST   
 
 
aspartate transaminase 
AUC  
 
 
area under the curve 
BUN  
 
 
blood urea nitrogen 
CFR 
 
 
 
Code of Federal Regulations 
Cmin 
 
 
 
minimum plasma concentration 
Cmax 
 
 
 
maximum plasma concentration 
CSF 
 
 
 
cerebrospinal fluid 
CSI 
 
 
 
Cassava Sciences, Inc. 
C-SSRS 
 
 
Columbia-Suicide Severity Rating Scale 
DSMB  
 
 
Data Safety Monitoring Board 
ECG  
 
 
electrocardiogram 
eCRF  
 
 
electronic case report form 
EDTA  
 
 
ethylenediaminetetraacetic acid 
ELISA  
 
 
enzyme-linked immunosorbent assay 
FDA  
 
 
Federal Drug Association 
FIH 
 
 
 
first in human 
FLNA  
 
 
filamin A 
GCP  
 
 
good clinical practice 
GDS  
 
 
geriatric depression scale 
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 
 
 
 
Institutional Review Board 


Cassava Sciences, Inc. 
Clinical Protocol PTI-125-04 
Simufilam (PTI-125), A small molecule to treat AD 
June 11, 2021 
Amendment #7 
 
 
 
Page 11 of 39 
 
 
CONFIDENTIAL 
LDH   
 
 
lactose dehydrogenase 
LOQ  
 
 
limit of quantitation 
MI 
 
 
 
myocardial infarction 
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 
NfL 
 
 
 
neurofilament light chain 
NPI 
 
 
 
neuropsychiatric inventory 
OTC  
 
 
over-the-counter 
PK 
 
 
 
pharmacokinetics 
PTI-125 
 
 
small molecule drug candidate to treat AD 
PTI-125Dx 
 
 
blood-based diagnostic/biomarker candidate 
RBC  
 
 
red blood cell 
SAD  
 
 
single ascending dose 
SAE 
 
 
 
serious adverse event 
SOP 
 
 
 
standard operating procedure 
TLR4  
 
 
toll-like receptor 4 
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-125-04 
Simufilam (PTI-125), A small molecule to treat AD 
June 11, 2021 
Amendment #7 
 
 
 
Page 12 of 39 
 
 
CONFIDENTIAL 
2. INTRODUCTION 
2.1. MECHANISM OF ACTION 
Cassava Sciences, Inc. is developing simufilam, a novel drug candidate designed to treat 
and slow the progression of Alzheimer’s disease (AD). Simufilam 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 Simufilam 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. This signaling requires the recruitment of altered FLNA to this 
receptor. Second, altered FLNA also links to 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 in AD brain. In two AD mouse models and in postmortem human AD brain 
tissue, simufilam 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 
Simufilam also improved synaptic plasticity and reduced tau hyperphosphorylation, 
amyloid deposits, neurofibrillary tangles and inflammatory cytokine release.2,3 We 
therefore expect simufilam both to improve cognition and to slow AD progression. Both 
mouse models used a dose of 20 mg/kg/day (equivalent to 60 mg/m2/day).  
2.2. SAFETY PHARMACOLOGY AND TOXICOLOGY 
A robust nonclinical ADME, safety pharmacology, and general and genetic toxicology 
program has been conducted with simufilam. In vitro metabolic profiling showed 
minimal metabolism across several species including humans. Simufilam 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.  
 


Cassava Sciences, Inc. 
Clinical Protocol PTI-125-04 
Simufilam (PTI-125), A small molecule to treat AD 
June 11, 2021 
Amendment #7 
 
 
 
Page 13 of 39 
 
 
CONFIDENTIAL 
Simufilam was tested in single dose and repeat dose oral toxicity studies in rats and dogs. 
A 6-month repeat dose oral toxicity study in rat (PTI-125-NC-049) used the same doses 
as a 28-day study (50, 500 and 1000 mg/kg/day), which found 500 mg/kg/day to be the 
no observable adverse effect level (NOAEL). In the 6-month study, 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). A second 
ongoing 6-month repeat dose oral toxicity study in rat will more accurately determine the 
6-month NOAEL in rat. Doses are vehicle and 125 and 250 mg/kg/day.  
In a 9-month toxicity study in dog (PTI-125-NC-050), the no observable effect level 
(NOEL) of simufilam was 25 mg/kg. The 200 mg/kg (high) dose was decreased to 150 at 
1 month due to bodyweight loss thought unsustainable for 9 months. Clinical signs were 
salivation and a few instances of muscle fasciculations. There were no pathology 
findings, but the high dose was considered adverse due to two unexplained deaths. The 
75 mg/kg/day NOAEL provides 38- and 19-fold safety margins by Cmax and AUC over 
the 100 mg b.i.d. dose in patients. 
2.3. CLINICAL STUDIES 
2.3.1. 
A first-in-human Single Ascending Dose clinical trial 
A first-in-human, 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). 
2.3.2. 
First-in-patient multidose clinical trial in mild-to-moderate AD patients 
In a Phase 2a 28-day study, 13 mild-to-moderate AD patients received simufilam 100 mg 
b.i.d. as oral tablets. Patients were MMSE ≥ 16 and ≤ 24, age 50-85, with a CSF total 
tau/Aβ42 ratio ≥ 0.30. A second CSF sample was collected on Day 28, allowing 
assessment of change from baseline in biomarkers using commercial ELISA kits. All 8 
biomarkers that are elevated in AD were significantly reduced from baseline (Fig. 1).4 
Aβ42, which is low in AD, was increased slightly but non-significantly. Reduced 
inflammatory cytokines and YKL-40 indicated reduced neuroinflammation. A reduced 
neurodegenerative drive was suggested by reductions in neurogranin, neurofilament light 


Cassava Sciences, Inc. 
Clinical Protocol PTI-125-04 
Simufilam (PTI-125), A small molecule to treat AD 
June 11, 2021 
Amendment #7 
 
 
 
Page 14 of 39 
 
 
CONFIDENTIAL 
chain, and total tau. The robust reduction in phospho-tau (P-Tau181) confirms the 
mechanism of action of simufilam. Simufilam was safe and well tolerated in all patients. 
Fig. 1   Phase 2a Mean Change from Baseline to Day 28 in CSF biomarkers (±SEM) 
 
2.3.3. 
Double-blind placebo-controlled clinical trial in mild-to-moderate AD patients 
A Phase 2b randomized, placebo-controlled clinical trial of simufilam 50 or 100 mg 
tablets or placebo (1:1:1) enrolled 64 mild-to-moderate AD patients with MMSE 16-26. 
Both 50 and 100 mg doses significantly improved eleven CSF biomarkers of AD 
pathology, neurodegeneration, neuroinflammation and blood-brain barrier integrity (Fig. 
2). CSF biomarker analyses were conducted blind to treatment and timepoint by an 
outside lab, and screening and Day 28 samples for each patient were measured in 
triplicate in the same ELISA plates. Albumin and immunoglobulin G (IgG) were 
measured by immunoblotting and quantified by densitometric quantitation. These data 
suggest disease modification and replicate our Phase 2a results in a well-controlled study. 
Fig. 2   Phase 2b Mean Change from Baseline to Day 28 in CSF biomarkers (±SEM) 
 


Cassava Sciences, Inc. 
Clinical Protocol PTI-125-04 
Simufilam (PTI-125), A small molecule to treat AD 
June 11, 2021 
Amendment #7 
 
 
 
Page 15 of 39 
 
 
CONFIDENTIAL 
The secondary endpoints in the Phase 2b trial were two cognitive measures using the 
Cambridge Neuropsychological Test Automated Battery. Patients were assessed on the 
Paired Associate Learning (PAL) test, measuring episodic memory, and a test of spatial 
working memory. The primary outcome measures for each were total errors, with errors 
imputed for more difficult levels not reached in the PAL test. Simufilam produced 
encouraging effect sizes (calculated by Hedge’s g for group sizes of 20), suggesting 
cognitive enhancement (Fig. 3). Effect sizes versus placebo for the test of episodic 
memory were 37% and 23% for the 50 and 100 mg groups, respectively, after removing 
the most and least impaired subjects by baseline score. For spatial working memory, 
effect sizes were 17% and 46% for these respective dose groups. Cognitive enhancement 
by simufilam is supported by preclinical data showing improved function of α7nAChR, 
NMDAR and insulin receptors and improved synaptic plasticity in 3xTg AD mice and in 
postmortem human AD brain tissue. In both Phase 2 clinical trials, simufilam was well 
tolerated and no patients discontinued due to AEs.  
Fig. 3   Phase 2b Mean Change from Baseline to Day 28 in Total Errors in Memory Test 
 
2.3.4. 
Open-label safety clinical trial in mild-to-moderate AD patients 
We are conducting a 1-year, open-label safety study in mild-to-moderate AD patients. 
The study was meant to offer open-label drug to participants of our two Phase 2 studies 
and is also enrolling new patients. In the first 50 patients to reach 6 months, simufilam 
improved cognition and behavior at 1, 3 and 6 months. ADAS-Cog11 scores improved 
1.6 points and NPI scores improved 1.3 points from baseline at 6 months. Mean baseline 
MMSE was 22.1, and mean ADAS-Cog11 was 15.5 for these 50 patients. 


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3. STUDY OBJECTIVES 
The objectives of this study are to establish 1-year safety and to investigate the effect of 
simufilam on biomarkers, cognition and neuropsychiatric symptoms during 12-month 
repeat-dose oral administration in mild-to-moderate AD patients, 50-85 years of age. An 
objective of the 6-month randomized withdrawal is to determine whether mild-to-
moderate AD patients, age 50-85, who have completed a one-year open-label study of 
100 mg b.i.d. simufilam and who continue with active dosing will show slower decline on 
ADAS-Cog11 and the NPI than patients who withdraw from this treatment. 
4. SUMMARY OF STUDY DESIGN 
The first 12 months is an open-label treatment of simufilam 100 mg b.i.d. for patients 
who completed prior Phase 2 studies PTI-125-02 and PTI-125-03. New patients are 
included so that up to 200 patients are enrolled in this study. Month 12 to Month 18 is a 
randomized withdrawal phase; patients will be randomized to continue taking simufilam 
100 mg b.i.d. or matching placebo. Month 18 to Month 24 will be an additional 6 months 
of open-label simufilam 100 mg b.i.d. Simufilam and placebo will be administered as 
coated oral tablets. Patients who were enrolled prior to this amendment can continue 
upon reconsenting to the randomized withdrawal and final 6-month open-label portion.    
All patients will provide consent to enroll into this study. Unless patients have a prior 
positive amyloid PET scan, MRI showing hippocampal volume loss or other prior 
evidence of AD, patients will undergo a CSF draw (if all other screening criteria are met) 
to confirm a total tau/Aβ42 ratio ≥ 0.28.  
Patients will report to the clinic in the morning of Day 1. Prior to dosing, patients will 
complete the following baseline measures: ECG, vital signs, clinical labs, urinalysis, 
listen to heart and lungs, ADAS-Cog11, neuropsychiatric inventory (NPI), geriatric 
depression scale (GDS), and the C-SSRS. A blood sample will be collected for plasma-
based biomarkers and genetic testing.  
Patients will return to the clinic every month through Month 3 and every 1.5 months 
through Month 12. Visits on Months 4.5, 7.5 and 10.5 will include vital signs, listening to 
heart and lungs, AE monitoring, C-SSRS, and drug dispensation and accountability only 
and may be conducted by telemedicine, based on the judgement of the Investigator. After 
Month 12, visits will be on Months 13, 15, 18, 21 and 24. Patients completing Month 12 
prior to availability of drug supply for the randomized withdrawal phase will continue 
with active treatment until drug supply is ready and therefore will have an additional 
“Withdrawal Day 1” visit before resuming with the Month 13 visit one month later. 


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Clinical Protocol PTI-125-04 
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PK blood samples will be obtained in the morning before dosing at return visits on 
Months 15 and 18.  
Blood draws for clinical laboratory testing and urine collection for urinalysis will be 
performed at Day 1 and Months 1, 2, 3, 6, 9, 12, 15, 18, 21 and 24. Safety assessments of 
vital signs and listening to heart and lungs will be conducted at all visits. ECGs will be 
conducted on Day 1 and Months 1, 3, 6, 9, 12, 18 and 24.  
For plasma biomarkers, plasma samples will be collected on Day 1 prior to dosing and on 
Months 3, 6, 9, 12, 15, 18, 21 and 24. Plasma markers include SavaDx, the 
complementary diagnostic/biomarker, and a subset of CSF biomarkers (NfL, 
neurogranin, total tau, Aβ42 and YKL40). For the first 50 patients who provided a 
screening CSF sample, an additional CSF sample will be collected at Month 6 or Month 
12 (25 patients each Month 6 and Month 12). This sample will be used to assess CSF 
biomarker changes. These CSF draws will, however, become OPTIONAL after 50 
patients have provided either a Month 6 or Month 12 CSF sample. Further, these optional 
Month 6 or Month 12 samples should NOT be obtained from patients who did not 
provide a CSF sample at screening. 
An independent Data Safety Monitoring Board (DSMB), will meet periodically to review 
patient safety assessments and determine if dosing may continue. 
5. SUBJECT SELECTION 
5.1. STUDY POPULATION 
Up to 200 patients will be enrolled in the study (male and female).  
5.2. INCLUSION CRITERIA 
All patients must comply with the following Inclusion Criteria:  
1. 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. 
2. Patient has a caregiver or legal representative responsible for administering the drug 
and recording the time. 
3. Ages ≥ 50 and ≤ 85 years  


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4. 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. 
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. 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 SavaDx. 
12. MMSE-2 score ≥ 16 and ≤ 26 at screening, OR if > 26, must have evidence of AD 
pathology such as a prior CSF total tau/Aβ42 ratio ≥ 0.28, an amyloid positive PET 
scan or hippocampal volume loss consistent with AD.  
5.3. EXCLUSION CRITERIA 
Patients meeting any of the following Exclusion Criteria will be excluded from the study: 
1. Anything that in the opinion of the Investigator would preclude participation in a 2-
year study. 
2. BMI < 18.5 
3. Positive urine drug screen. 
4. Positive HIV, HCV or HbsAg screen. 
5. Suicidality on C-SSRS 
6. Exposure to an experimental drug other than simufilam, experimental biologic or 
experimental medical device within 3 months before screening 
7. A medical condition that would interfere with a lumbar puncture  
8. Residence in a skilled nursing facility and requiring 24 h care. 
9. Clinically significant laboratory test results 


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10. Clinically significant untreated hypothyroidism (if treated, thyroid-stimulating 
hormone level and thyroid supplementation dose must be stable for at least 6 months 
before screening) 
11. Insufficiently controlled diabetes mellitus, including requiring insulin or metformin 
>1000 mg/day. 
12. Renal insufficiency (serum creatinine > ULN and clinically significant in the opinion 
of PI and/or Sponsor OR eGFR <60 ml/min/m2 as estimated by either the MDRD or 
CKD-EPI equation) 
13. 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) 
14. History of ischemic colitis or ischemic enterocolitis 
15. Unstable medical condition that is clinically significant in the judgment of the 
investigator 
16. Alanine transaminase (ALT) or aspartate transaminase (AST) > ULN or total 
bilirubin > ULN and clinically significant in the opinion of PI and/or Sponsor.  
17. History of myocardial infarction or unstable angina within 6 months before screening 
18. History of more than 1 myocardial infarction within 5 years before screening 
19. Clinically significant cardiac arrhythmia (including atrial fibrillation), 
cardiomyopathy, or cardiac conduction defect (patients with a pacemaker are 
acceptable) 
20. Symptomatic hypotension, or uncontrolled hypertension  
21. Clinically significant abnormality on screening electrocardiogram (ECG), including 
but not necessarily limited to a confirmed QTc (Fridericia correction method) value ≥ 
450 msec for males or ≥ 470 msec for females.  
22. Stroke within 18 months before screening, or history of a stroke concomitant with 
onset of dementia 
23. History of brain tumor or other clinically significant space-occupying lesion on CT or 
MRI 
24. Head trauma with clinically significant loss of consciousness within 12 months before 
screening or concurrent with the onset of dementia 
25. Onset of dementia secondary to cardiac arrest, surgery with general anesthesia, or 
resuscitation 
26. Specific degenerative CNS disease diagnosis other than AD (e.g., Huntington's 
disease, Creutzfeld-Jacob disease, Down's syndrome, Frontotemporal Dementia, 
Parkinson's disease) 


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June 11, 2021 
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27. Wernicke's encephalopathy 
28. Active acute or chronic CNS infection 
29. Donepezil 23 mg or greater QD currently or within 3 months prior to enrollment 
30. Discontinued AChEI < 30 days prior to enrollment 
31. 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 enrollment 
32. 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 
enrollment 
33. 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 enrollment 
34. Immunosuppressants, including systemic corticosteroids, if taken in clinically 
immunosuppressive doses (Steroid use for allergy or other inflammation is 
permitted.) 
35. Antiepileptic medications if taken for control of seizures 
36. Chronic intake of opioid-containing analgesics 
37. Sedating H1 antihistamines 
38. Nicotine therapy (all dosage forms including a patch), varenicline (Chantix), or 
similar therapeutic agent within 30 days before screening 
39. Clinically significant illness within 30 days of enrollment  
40. History of significant neurological, hepatic, renal, endocrine, cardiovascular, 
gastrointestinal, pulmonary, or metabolic disease  
41. Loss of a significant volume of blood (> 450 mL) within 4 weeks prior to enrollment 
42. COVID-19 infection within 3 months of screening 
6. STUDY DRUG 
6.1. STUDY DRUG PHYSICAL DESCRIPTION AND PREPARATION 
Investigational simufilam and placebo will be supplied by Cassava Sciences as coated 
tablets in 70- or 200-count bottles. Several days of extra tablets are included in each 
bottle to allow flexibility of scheduling visits. 


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Clinical Protocol PTI-125-04 
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All remaining study drug will be returned to the sponsor or designee. 
6.1.1. Storage 
Bottles of study drug 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 receive 100 mg simufilam b.i.d. during the open-label portions of the 
study and either 100 mg simufilam or matching placebo during the randomized 
withdrawal portion of the study. Simufilam or placebo tablets should be at least 1 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 at entry. 
7. STUDY PROCEDURES 
Appendix A presents the Schedule of Activities. 
Prior to any study-related activities, the Informed Consent Form (ICF) must be signed 
and dated by the patient or legal representative. The format and content of the ICF must 
be agreed upon by the Principal Investigator(s), the appropriate IRB and the Sponsor 
(or designee). The signed and dated ICF must be retained by the Investigator in the 
subject's file. 
7.1. 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: 
 


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Clinical Protocol PTI-125-04 
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• ALT or AST ≥ 3 x ULN.  
• ALT or AST ≥ 2.5 x ULN and total bilirubin ≥ 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).  
• ALT or GGT ≥ 2.5 x ULN that persists for ≥4 weeks. 
 
In the event of discontinuation due to liver abnormalities, the patient will be 
appropriately investigated to determine the potential cause and referred to a physician 
experienced in the treatment of hepatic disorders. 
 
An additional stopping criterion will be bodyweight loss of ≥ 2 kg resulting in a BMI < 
18.5.  
 
7.2. EVALUATIONS BY VISIT 
7.2.1. Screening Visit 1 (Days -29 to 0) 
Patients who completed PTI-125-02 < 60 days of study start will not be rescreened 
but will sign the ICF on Day 1 or earlier for this open-label extension. 
For all other patients, the following will be completed in the screening visit: 
• Informed Consent  
• Review of Inclusion and Exclusion Criteria 
• Medical history 
• Review of concomitant medications 
• Confirmation that the patient is either fully vaccinated for the COVID-19 
virus at least 2 weeks prior to first dose of simufilam, or a positive serology 
test for the COVID-19 virus with no current symptoms 
• If needed, CT scan to confirm I/E criteria, per investigator judgement  
• MMSE-2 evaluation (prior patients do not need to meet 16 to 26 range) 
• 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. 


Cassava Sciences, Inc. 
Clinical Protocol PTI-125-04 
Simufilam (PTI-125), A small molecule to treat AD 
June 11, 2021 
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7.2.2. Screening Visit 2 (Days -28 to 0) 
This CSF draw is required for all NEW patients meeting Screening Visit 1 criteria 
who do not have a prior positive amyloid PET scan or MRI showing hippocampal 
volume loss OR prior CSF biomarkers confirming AD. If Screening Visit 2 and Study 
Day 1 visit are combined, the CSF sample collection will occur 1-3 h after dosing and 
after the MMSE-2, ADAS-Cog11, NPI and GDS testing has been completed. 
• CSF sample collection (5 mL)  
• CSF samples should be held at the study site frozen at -70°C, pending 
shipping instructions from the Sponsor. 
 
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), and 
weight 
• Listen to heart and lungs 
• ADAS-Cog11, NPI, GDS testing and C-SSRS – Since Last Visit version. If 
the C-SSRS indicates imminent risk for suicidality, defined as the patient 
positively endorsing questions 4 or 5 of the suicidal ideation section or any 
suicidal behavior questions, discontinue study drug and refer for appropriate 
care. 
• Blood sample collection for clinical laboratory tests 
• Plasma sample collection for SavaDx and other plasma biomarkers. 
• ECG 
 
Patients will be administered 100 mg simufilam b.i.d. 1-2 h before or after a meal.  
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 AEs until discharge from the clinic. 
Upon investigator judgment, patients will be discharged with their supply of study 


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Clinical Protocol PTI-125-04 
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drug until the next visit. They will be instructed to take study drug twice daily, at least 
1-2 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. 
All follow-up visits can be +/- five (5) days for flexibility. For all follow-up visits 
except Months 4.5, 7.5 and 10.5, 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.  
7.2.4. Follow-up Visits on Months 1, 3, 9, 13, 15, 21 
Patients will return to clinic in the morning before taking their morning dose. 
Within 30 min prior to dosing, the following assessments will be conducted: 
• Blood sample collection for PK assessment (for Cmin – Month 15 only) 
• Clinical laboratory tests (blood and urine) (All visits except Month 13) 
• Plasma sample collection (from 8 mL whole blood) for SavaDx and other 
plasma biomarkers (All visits except Months 1 and 13) 
 
After dose, the following assessments will be conducted: 
• Vital signs (blood pressure, temperature, pulse and respiratory rate), and 
weight 
• Listen to heart and lungs 
• ECG (Month 1 only) 
• Adverse event monitoring 
• ADAS-Cog11, NPI, GDS and C-SSRS – Since Last Visit version. If the C-
SSRS indicates imminent risk for suicidality, defined as the patient positively 
endorsing questions 4 or 5 of the suicidal ideation section or any suicidal 
behavior questions, discontinue study drug and refer for appropriate care. 
• Saliva collection for genetic testing (Month 15 Visit only) 
 
7.2.5. Follow-up Visit on Month 2 
Patients will return to clinic in the morning before taking their morning dose. 
Within 30 min prior to dosing, the following assessments will be conducted: 
• Clinical laboratory tests (blood and urine) 
 
After dose, the following assessments will be conducted: 
• Vital signs (blood pressure, temperature, pulse and respiratory rate), and 
weight  


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Clinical Protocol PTI-125-04 
Simufilam (PTI-125), A small molecule to treat AD 
June 11, 2021 
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• Listen to heart and lungs 
• Adverse event monitoring 
• C-SSRS – Since Last Visit version. If the C-SSRS indicates imminent risk for 
suicidality, defined as the patient positively endorsing questions 4 or 5 of the 
suicidal ideation section or any suicidal behavior questions, discontinue study 
drug and refer for appropriate care. 
 
7.2.6. Follow-up Visits on Months 4.5, 7.5 and 10.5 
Patients will return to clinic at any time of day. The visit may be conducted by 
telemedicine, based on the judgement of the Investigator. 
The following assessments will be conducted: 
• Vital signs (blood pressure, temperature, pulse and respiratory rate), and 
weight  
• Listen to heart and lungs 
• Adverse event monitoring 
• C-SSRS – Since Last Visit version. If the C-SSRS indicates imminent risk for 
suicidality, defined as the patient positively endorsing questions 4 or 5 of the 
suicidal ideation section or any suicidal behavior questions, discontinue study 
drug and refer for appropriate care. 
 
7.2.7. Follow-up Visits on Month 6 and 18 
Patients will return to the clinic in the morning on the Month 6 Visit. Those patients 
undergoing a CSF draw will take their morning dose upon arrival (time of dosing to 
be recorded). 
Patients will return to clinic in the morning before taking their morning dose. 
Within 30 min prior to dosing, the following assessments will be conducted: 
• Blood sample collection for PK assessment (for Cmin – Month 18 only) 
• Clinical laboratory tests (blood and urine) 
• Plasma sample collection (from 8 mL whole blood) for SavaDx and other 
plasma biomarkers. 
 
After dose, the following assessments will be conducted: 
• Vital signs (blood pressure, temperature, pulse and respiratory rate), and 
weight  
• Listen to heart and lungs 


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Clinical Protocol PTI-125-04 
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June 11, 2021 
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• Adverse event monitoring 
• ECG 
• ADAS-Cog11, NPI, GDS, and C-SSRS – Since Last Visit version. If the C-
SSRS indicates imminent risk for suicidality, defined as the patient positively 
endorsing questions 4 or 5 of the suicidal ideation section or any suicidal 
behavior questions, discontinue study drug and refer for appropriate care. 
• CSF sample collection at Month 6 (time post-dose to be recorded) only for 
the first 25 patients with a baseline CSF. (The next 25 patients with a 
baseline CSF will have CSF drawn at Month 12). Month 18 CSF draw is 
OPTIONAL for patients who provided a Month 6 or Month 12 CSF and is not 
an option for any other patients. 
 
7.2.8. Month 12 and 24 Follow-up Visits 
Patients will return to clinic in the morning before taking their morning dose. Patients 
who were enrolled prior to this amendment can terminate after completing the 
original 12-month open-label portion or can reconsent to the randomized withdrawal 
and final 6-month open-label portion.  Month 12 morning dose in the clinic will be 
from Open-Label Period 1 bottle.  Month 12 evening dose will be from the 
Randomized Period 2 bottle. 
Within 30 min prior to dosing, the following assessments will be conducted: 
• Clinical laboratory tests (blood and urine) 
• Plasma sample collection (from 8 mL whole blood) for SavaDx and other 
plasma biomarkers. 
 
After dose, the following assessments will be conducted: 
• Full physical exam  
• Adverse event monitoring 
• MMSE-2 
• ECG 
• ADAS-Cog11, NPI, GDS, and C-SSRS – Since Last Visit version. If the C-
SSRS indicates imminent risk for suicidality, defined as the patient positively 
endorsing questions 4 or 5 of the suicidal ideation section or any suicidal 
behavior questions, discontinue study drug and refer for appropriate care. 
• CSF sample collection at Month 12 (time post-dose to be recorded) for 
patients with a screening CSF who did not provide a CSF sample at 
Month 6. For those patients who provided a Month 6 CSF, this Month 12 
CSF will be OPTIONAL. After 50 patients have provided either Month 6 


Cassava Sciences, Inc. 
Clinical Protocol PTI-125-04 
Simufilam (PTI-125), A small molecule to treat AD 
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CONFIDENTIAL 
or Month 12 CSF, no additional patients will have CSF drawn after 
screening. No CSF will be drawn at Month 24. 
 
For patients undergoing a CSF draw, CSF sample collection (5 mL) will occur 1-3 h 
after dosing and after the MMSE, ADAS-Cog11, NPI and GDS testing has been 
completed. These samples will be tested for CSF biomarkers.  
 
Patients who complete Month 12 prior to availability of drug supply for the 
randomized withdrawal phase (Months 12 – 18) will be dispensed additional open-
label simufilam and will return for a Withdrawal Day 1 Visit as appropriate. 
 
7.2.9. 
Withdrawal Day 1 Visit – If Needed 
This additional visit is only for patients who complete Month 12 prior to 
availability of drug supply for the randomized withdrawal phase (Months 12 – 
18) and who have been dispensed additional open-label simufilam while waiting. 
Patients will return to the clinic at any time of day for the following assessments: 
• ADAS-Cog11, NPI, GDS, and C-SSRS – Since Last Visit version. If the C-
SSRS indicates imminent risk for suicidality, defined as the patient positively 
endorsing questions 4 or 5 of the suicidal ideation section or any suicidal 
behavior questions, discontinue study drug and refer for appropriate care. 
 
These patients will return to the clinic one month later for the Month 13 visit and 
continue with the rest of the scheduled visits.  
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 Months 1, 2, 3, 6, 9, 12, 15, 18, 21 and 24:  
• Hematology:  white blood cell (WBC) count with differential, red blood cell 
(RBC) count, hemoglobin, hematocrit, platelet count. 
• 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, alanine transaminase (ALT), aspartate transaminase (AST), 
gamma glutamyl transpeptidase (GGT), lactose dehydrogenase (LDH). 
• Urinalysis: color, specific gravity, pH, protein, sugar, ketones, occult blood, 
creatinine clearance calculation by Cockcroft-Gault equation (without 
requiring a 24-h urine collection). 


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7.3.2. Preparation of Whole Blood Samples for Lymphocyte and Plasma Biomarkers 
Whole blood samples will be collected on Day 1 and Months 3, 6, 9, 12, 15, 18, 21 
and 24. Blood samples (8 mL total) will be drawn into a Vacutainer® tube 
containing K2EDTA. As advised by Sponsor, the blood may be spun down to 
separate the plasma (all new patients) OR shipped as whole blood (patients with 
prior samples shipped as whole blood. These patients with prior samples shipped as 
whole blood will continue to have samples shipped as whole blood only through 
Month 12. Samples at Months 15, 18 21 and 24 will be spun to plasma). Plasma 
should be frozen at -70°C and held until advised by the Sponsor to ship to: Dr. John 
Xu, Abilene Christian University, HAL Research Center Room 201, 1201 East 
Ambler Ave, Abilene, TX 79699. Whole blood should be shipped immediately at 4°C 
to: Dr. Hoau-Yan Wang, CUNY School of Medicine, SOM CDI 3370, 85 St. Nicolas 
Terrace, New York, NY 10027, or another lab.  Do not ship samples on Friday.  
7.3.3. Preparation of Plasma Samples for Pharmacokinetic Determination  
At each blood collection for PK (pre-dose samples for Cmin at Months 15 and 18 
only, 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 between 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 -20°C or below until analysis.  
At the end of the study, 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 simufilam with a validated assay. The second 
set of samples will be shipped separately once receipt of the first set is confirmed.  
  
7.3.4. Preparation of CSF samples 
CSF will be collected and aliquoted into 5 ml Screw-Cap LoBind Eppendorf® tubes 
(# 0030122356). CSF samples should be split into two aliquots of 2.5 mL. Samples 
will be held frozen at -70°C.  
When notified by Sponsor, samples will be shipped to Dr. Wang at CUNY (address 
above) for biomarker analyses or another lab. Samples will be shipped frozen on dry 
ice (Mon – Wed). 
7.3.5. Collection of Cheek Swab Saliva Samples for Genetic Testing 
Saliva samples will be collected only at Month 15. Patients will refrain from eating or 
drinking 1 h prior to saliva collection. Each patient will be instructed to spit into a 
saliva collection tube. The saliva will be stored at -20°C until instructed to ship by the 
Sponsor. 


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Clinical Protocol PTI-125-04 
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CONFIDENTIAL 
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 Sponsor 
discretion. 
 
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), weight, full 
physical examination, clinical laboratory tests, ECG, use of concomitant 
medications, and adverse events) should be obtained at discharge prior to release. 
• Collection of plasma for biomarkers  
• MMSE-2 
• ADAS-Cog11, NPI and GDS (If the patient scores above 4 on the GDS assessment, 
a referral for further follow-up with the patient’s primary care physician or 
psychiatrist is required. In addition, immediately administer the C-SSRS. If the C-
SSRS indicates imminent risk for suicidality, defined as the patient positively 
endorsing questions 4 or 5 of the suicidal ideation section or any suicidal behavior 
questions, immediately contact the sponsor.) 
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, 


Cassava Sciences, Inc. 
Clinical Protocol PTI-125-04 
Simufilam (PTI-125), A small molecule to treat AD 
June 11, 2021 
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CONFIDENTIAL 
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 electronic Case Report Form (eCRF) 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 eCRF 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 eCRF in appropriate medical terminology. The 
severity and the relationship to the study drug will be determined and reported on the 
CRF (see below). 
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. 


Cassava Sciences, Inc. 
Clinical Protocol PTI-125-04 
Simufilam (PTI-125), A small molecule to treat AD 
June 11, 2021 
Amendment #7 
 
 
 
Page 31 of 39 
 
 
CONFIDENTIAL 
• 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 re-challenge with the study drug. 
These three categories are based on the Investigator's clinical judgment and 
consideration of various factors such as the subject's report, the timing of the AE in 
relationship 
to 
study 
drug 
administration/discontinuation, 
the 
Investigator's 
observations and the Investigator's prior experience. The relationship of the AE to the 
study drug will be recorded in the 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 
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. 


Cassava Sciences, Inc. 
Clinical Protocol PTI-125-04 
Simufilam (PTI-125), A small molecule to treat AD 
June 11, 2021 
Amendment #7 
 
 
 
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CONFIDENTIAL 
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. 
 
All SAEs must be reported immediately (within 24 h of learning of the event) by 
telephone or notification via email through the EDC system to: 
 
Nadav Friedmann, PhD, MD 
Cassava Sciences, Inc.  
Email: nfriedmann@cassavasciences.com 
Phone:    925-788-4585 
 
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 sent within five (5) working days to the 
medical monitor. The Sponsor will report SAEs to the IRB and FDA as required. 
 
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.  
 
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 ICF. 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. ANALYSIS POPULATIONS 
All patients who receive study medication will be included in safety analyses. All 
patients who have sufficient data for biomarker, ADAS-Cog11, NPI and GDS analyses 
will be included in the analysis population for each measure individually.  


Cassava Sciences, Inc. 
Clinical Protocol PTI-125-04 
Simufilam (PTI-125), A small molecule to treat AD 
June 11, 2021 
Amendment #7 
 
 
 
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CONFIDENTIAL 
10.2. PHARMACOKINETIC PARAMETERS 
The only plasma PK parameters to be collected from this study are the Cmin values from 
blood samples taken prior to dosing at Months 15 and 18. 
 
10.3. STATISTICAL ANALYSIS 
Biomarker endpoints to be analyzed include: 1) CSF Aβ42, 2) CSF total tau 3) CSF p-
tau181, 4) CSF neurofilament light chain, 5) CSF neurogranin, 6) CSF sTREM2, 7) 
plasma neurofilament light chain, 8) plasma neurogranin, 9) plasma total tau, 10) 
plasma Aβ42, 11) SavaDx lymphocyte assay, 12) SavaDx plasma assay and 13) mTOR 
assay. These data will be analyzed by paired t test comparing baseline to Month 6 or 
Month 12. Other appropriate statistics may be performed to compare mild versus 
moderate patients. 
 
The ADAS-Cog11, NPI and GDS endpoints will be analyzed by linear regression with 
pre-planned comparisons of mild versus moderate patients. Other appropriate statistics 
may be performed. 
 
Month 12 to Month 18 ADAS-Cog11, NPI and GDS data will be analyzed by mixed 
model repeated measures (MMRM) analysis. Month 6/12 to Month 18 CSF biomarker 
data will be analyzed by ANCOVA for the effect of treatment with Month 6/12 value 
as the covariate, or by ANOVA.  
 
10.4. 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. 
10.5. SAMPLE SIZE 
Up to 200 patients may be enrolled in this study. Eligible patients include those who 
completed PTI-125-03 and PTI-125-02 as well as new patients. 
11. STUDY TERMINATION 
The study will be terminated following completion of the study or at any time at the 
discretion of the Sponsor. 


Cassava Sciences, Inc. 
Clinical Protocol PTI-125-04 
Simufilam (PTI-125), A small molecule to treat AD 
June 11, 2021 
Amendment #7 
 
 
 
Page 34 of 39 
 
 
CONFIDENTIAL 
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. 
All clinical information requested in this protocol will be recorded in the eCRFs 
provided by CSI. In case of error, the correction will be noted, initialed and dated. 
eCRFs must be reviewed and verified for accuracy by the Principal Investigator and 
signed-off before collection by the Sponsor (or CRO designee). Paper source 
documents, if used, will remain at the Investigator's site after study completion. 
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 ICF 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. 


Cassava Sciences, Inc. 
Clinical Protocol PTI-125-04 
Simufilam (PTI-125), A small molecule to treat AD 
June 11, 2021 
Amendment #7 
 
 
 
Page 35 of 39 
 
 
CONFIDENTIAL 
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 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. 


Cassava Sciences, Inc. 
Clinical Protocol PTI-125-04 
Simufilam (PTI-125), A small molecule to treat AD 
June 11, 2021 
Amendment #7 
 
 
 
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CONFIDENTIAL 
12.6. INFORMED CONSENT FORM 
The Sponsor (or designee) must review the Investigator's proposed ICF prior to IRB 
submission for approval. An IRB-approved copy of the Informed Consent Form is 
forwarded to the Sponsor. 
The ICF 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 ICF must be signed and dated 
before the subject enters the study. The original ICF and any amended ICF, signed and 
dated, must be retained in the subject's file at the study site and a copy must be given to 
the subject. 
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 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. 
• Promptly report to 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-125-04 
Simufilam (PTI-125), A small molecule to treat AD 
June 11, 2021 
Amendment #7 
 
 
 
Page 37 of 39 
 
 
CONFIDENTIAL 
14. REFERENCES 
1. 
Wang H-Y, Pei Z, K.-C. Lee K-C, et al. PTI-125 Reduces Biomarkers of Alzheimer’s Disease 
in Patients. J Prevent Alzheimer's Disease 2020; doi:10.14283. 
2. 
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. 
3. 
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. 
4. 
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. 
5. 
Hansson O, Seibyl J, Stomrud E, et al. CSF biomarkers of Alzheimer’s disease concord with 
amyloid-β PETand predict clinical progression: A study of fully automated immunoassays in 
BioFINDER and ADNI cohorts. Alzheimer's Dement 2018;14:1470-81. 
 


Cassava Sciences, Inc. 
Clinical Protocol PTI-125-04 
Simufilam (PTI-125), A small molecule to treat AD 
June 11, 2021 
Amendment #7 
 
 
 
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CONFIDENTIAL 
15. APPENDIX A 
Events Schedule 
PROCEDURE 
Screen 
Visit 1 
Screen 
Visit 2 
DAY 
1 
Month 
1 
Months  
2, 4.5, 7.5 
& 10.5 
Months  
3, 9, 15 
& 21  
Month 
13 
Months 
6 & 18 
Month 
12 & 
24 
 ( With-
drawal 
Day 1 ) 
Informed 
Consent a 
X 
 
 
 
 
 
 
 
(X)  
 
Medical  
histories 
X 
 
 
 
 
 
 
 
 
 
ECG  
X 
 
X 
X 
 
 
 
X 
X 
 
CT scan  
(X) 
 
 
 
 
 
 
 
 
 
Vital signs d 
X 
 
X 
X 
(X) 
X 
X 
X 
X 
 
Physical 
examination 
X 
 
* 
* 
(*) 
* 
* 
* 
X 
 
Biochemistry, 
hematology, 
urinalysis 
X 
 
X 
X 
Month 2 
only 
X 
 
X 
X 
 
MMSE-2 
X 
 
 
 
 
 
 
 
X 
 
Saliva 
collected for 
genetic testing 
 
 
 
 
 
Month 
15 only 
 
 
 
 
HCV, HBsAg 
& HIV screen 
X 
 
 
 
 
 
 
 
 
 
Urine drug 
screen 
X 
 
 
 
 
 
 
 
 
 
Drug 
dispensation 
 
 
X 
X 
X 
X 
 
X 
Xe 
X 
Pre-dose blood 
sample for PK  
 
 
 
 
 
Month 
15 only 
 
Month 
18 
only  
 
 
Adverse 
events 
 
 
X 
X 
X 
X 
X 
X 
X 
 
Blood draw 
for biomarkers 
 
 
X 
 
 
X 
 
X 
X 
 
CSF draw 
 
(X) b 
 
 
 
 
 
(X) c 
(X) c 
 
ADAS-Cog, 
NPI and GDS  
 
 
X 
X 
 
X 
X 
X 
X 
X 
C-SSRS 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
(  ) indicates performed per investigator judgement or not for all patients   
* Listen to heart and lungs  
a   Patients who did not initially consent for a 2-year study should be reconsented at their next study visit. 
b Patients who have a prior amyloid PET or other confirmation of AD can bypass this baseline CSF draw 


Cassava Sciences, Inc. 
Clinical Protocol PTI-125-04 
Simufilam (PTI-125), A small molecule to treat AD 
June 11, 2021 
Amendment #7 
 
 
 
Page 39 of 39 
 
 
CONFIDENTIAL 
c Only for patients with a baseline CSF. Patients with a baseline CSF have the option to do a Month 6 or 12 CSF draw. Month 18 CSF 
draw is an option only for patients who provided Month 6 or 12 CSF.  
d Include weight for BMI calculation 
e Drug dispensation only at Month 12 
NB: Withdrawal Day 1 is only for patients who complete Month 12 prior to drug supply availability for the randomized withdrawal.