Forward-Looking Statements & Safe Harbor
This presentation contains forward-looking statements, including statements made pursuant to the safe harbor provisions of the Private Securities Litigation Reform Act of
1995, that may include but are not limited to: our strategy and plans; the size and scope of our pivotal Phase 3 trial and its likelihood of success; the interpretation of clinical
data generated in interim analyses of an open-label study, plans to announce full study results and the timing thereof; plans to conduct ad hoc interim analyses on openlabel clinical data and the timing thereof; the initiation and progression of a scientific inquiry undertaken by CUNY and the publication of its results; the restoration of
scientific reputations; the treatment of Alzheimer’s disease; the status of current and future clinical studies with simufilam; the efficacy of simufilam in humans; the
publication of an analysis regarding the expected rate of cognitive decline in people with Alzheimer’s disease; our ability to expand therapeutic indications for simufilam
outside of Alzheimer’s disease; the development path for SavaDx and the use of alternative methods of detection; expected cash use in future periods; clinical data
presented at the 2021 Alzheimer's Association International Conference (AAIC), including a subsequent erratum regarding visual errors not caught in proofing; a technical
paper published in 2017 in Neurobiology of Aging and a subsequent erratum regarding a visual error not caught in proofing; verbal commentaries made by our employees;
and potential benefits, if any, of the our product candidates. These statements may be identified by words such as “may,” “anticipate,” “believe,” “could,” “expect,”
“forecast,” “intend,” “plan,” “possible,” “potential,” and other words and terms of similar meaning.
Drug development and commercialization involve a high degree of risk, and only a small number of research and development programs result in regulatory approval and
subsequent commercialization of a product. Our clinical results from earlier-stage clinical trials may not be indicative of full results or results from later-stage or larger scale
clinical trials and do not ensure regulatory approval. You should not place undue reliance on these statements or any scientific data we present or publish.
Such statements are based on our current expectations and projections about future events. Such statements speak only as of the date of this presentation and are subject
to a number of risks, uncertainties and assumptions, including, but not limited to, those risks relating to the ability to conduct or complete clinical studies on expected
timelines, to demonstrate the specificity, safety, efficacy or potential health benefits of our product candidates, potential health benefits, if any, of changes in levels of
biomarkers, the severity and duration of health care precautions given the COVID-19 pandemic, any unanticipated impacts of the pandemic on our business operations,
including those described in the section entitled “Risk Factors” in our Annual Report on Form 10-K for the year ended December 31, 2021 and future reports to be filed with
the SEC. The foregoing sets forth many, but not all, of the factors that could cause actual results to differ from expectations in any forward-looking statement. In light of
these risks, uncertainties and assumptions, the forward-looking statements and events discussed in this presentation are inherently uncertain and may not occur, and actual
results could differ materially and adversely from those anticipated or implied in the forward-looking statements. Accordingly, you should not rely upon forward-looking
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contained in this presentation. For further information regarding these and other risks related to our business, investors should consult our filings with the SEC, which are
available on the SEC's website at www.sec.gov
This presentation may also contain statistical data and drug information based on independent industry publications or other publicly available information. We have not
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representations as to the accuracy or completeness of such data or information. You are cautioned not to give undue weight to such data.
The content of this presentation is solely our responsibility and does not represent the official views of the National Institutes of Health (NIH).
2
Meet the Team
3
Michael Zamloot - SVP Technical Operations
Four FDA drug approvals prior to Cassava Sciences.
Lindsay H. Burns, PhD - SVP Neuroscience
Eric Schoen - Chief Financial Officer
Nadav Friedmann, PhD/MD - CMO, Board member
Eight FDA drug approvals prior to Cassava Sciences.
Remi Barbier - Chairman, President & CEO
Jim Kupiec, MD – Chief Clinical Development
Officer Two FDA drug approvals prior to Cassava Sciences. Sanford Robertson
Founding Partner - Francisco Partners and
Robertson Stephens & Company
Robert Gussin, PhD
Formerly, CSO & Corporate VP, Science
and Technology, Johnson & Johnson
Michael O’Donnell
Partner, Orrick LLP
Patrick Scannon, MD/PhD
Formerly, Founder & CSO/CMO -
XOMA Corporation
Independent Directors
Richard Barry
Founding Partner,
Portfolio Manager,
Eastbourne Capital
4
• More than 6 million Americans are living with
Alzheimer’s disease and this number may
rise to nearly 13 million by 2050, according
to the Alzheimer’s Association.
• Our scientific approach is unique, our
clinical data is highly differentiated.
• Science programs developed with support
from the National Institutes of Health (NIH).
• We are developing simufilam for the
proposed treatment of Alzheimer's
disease.
• Simufilam is a proprietary, oral drug
candidate, developed in-house with
academic collaborators.
• We are now conducting Phase 3 studies
with simufilam in patients with mild to
moderate Alzheimer’s.
Cassava Sciences Highlights
Our goal is to defeat Alzheimer’s disease.
• Simufilam is our proprietary, small molecule (oral)
drug candidate to treat Alzheimer’s disease and
other neurodegenerative diseases.
• Simufilam binds a single target, has a dual
mechanism of action:
• Reduces neurodegeneration and neuroinflammation.
• Published preclinical data and mechanism of action studies
support simufilam’s potential as a disease-modifying drug for
Alzheimer’s that also provides symptomatic improvement.
5
5
Introduction to Simufilam
Clinical/Regulatory Development of Simufilam
✓ 2017: Phase 1 dose-escalating safety study in human
volunteers.
✓ 2019: Phase 2a open-label safety study in Alzheimer’s
patients.
✓ 2020: Phase 2b randomized, placebo-controlled study in
Alzheimer’s patients.
✓ 2021: Interim analysis of open-label study in first 50
patients to complete 6, 9 & 12 months of treatment.
✓ 2021: End-of-Phase 2 meeting with FDA.
✓ 2021: Two FDA Special Protocol Assessments for on-going
Phase 3 studies.
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❑ Two Phase 3 studies in Alzheimer’s patients.
❑ Open-label study in Alzheimer’s patients.
❑ Randomized, placebo-controlled Cognition
Maintenance Study (CMS) in Alzheimer’s patients.
Completed On-going
Clinical Snapshot – Q1 2022
❑ Two Phase 3 studies in Alzheimer’s patients.
✓ 60 subjects are now enrolled in the Phase 3 program,
split almost equally among the two studies.
✓ Over 105 clinical trial sites across the U.S. and Canada
are now recruiting patients, with many sites activated in
Q1 2022.
✓ Our Phase 3 studies have a relatively long & rigorous
screening process to ensure only qualified patients who
meet all inclusion & exclusion criteria are successfully
enrolled. Approximately 170 patients are currently in
screening.
Our goal is to activate a total of 175 or more clinical trial
sites for the Phase 3 program,
including sites outside of North America.
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❑ Open-label study in Alzheimer’s patients.
✓ The open-label study is fully-enrolled (over 200 subjects).
✓ We expect all subjects will have completed drug treatment in ≈ 6 months.
Our goal is to complete the open-label study 2nd half
2022 and to announce data by year-end 2022.
❑ Randomized, placebo-controlled Cognition
Maintenance Study (CMS) in Alzheimer’s patients.
✓ CMS study is 69% enrolled towards a target enrollment of ≈ 100 subjects.
✓ All clinical data remains blinded.
Our goal is to complete enrollment for the CMS study
2
nd half 2022 and to announce data in 2023.
Phase 3 Program Other Clinical Studies
On-going Studies in Alzheimer’s disease
Science & Technology
8
Lindsay Burns, PhD – SVP Neuroscience
Nadav Friedmann, PhD/MD – Chief Medical Officer
Jim Kupiec, MD - Chief Clinical Development Officer
Mechanism of Action
The altered form of FLNA is a proteopathy in the AD brain.
Altered FLNA enables A�42 signaling via:
i. α7-nicotinic acetylcholine receptor (α7nAChR)
hyperphosphorylates tau
ii.Toll-like receptor 4 (TLR4)
releases inflammatory cytokines
Simufilam binds altered FLNA, restores its proper shape/function,
disables A�42 signaling via α7nAChR and TLR4.
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Proposed Mechanism of Action
The Target of Simufilam is Altered Filamin A (FLNA)
Filamin A (FLNA) is a scaffolding protein
highly expressed in the brain.
FLNA cross-links actin to provide structure and motility, but
also interacts with >90 proteins, influencing many signaling
pathways.
The Alzheimer's brain carries an altered form of FLNA.
Altered FLNA is critical to amyloid beta toxicity.
Through a single target,
simufilam reduces neurodegeneration and neuroinflammation.
10+ Year In-house Discovery/Development Program
10
1 2 3 4 5
<2008
Basic research around
neurobiology of Filamin A
(FLNA).
2009
Discovery that altered FLNA
links to �7nAChR when A�
signals.
2010
Screening/testing of compounds
that bind altered FLNA and
block �7nAChR/A� interaction.
2011
Simufilam (PTI-125)
binds altered FLNA with
high affinity, blocks
�7nAChR/A�
interactions. Preclinical
testing of simufilam.
2017 - present
IND filing. Clinical
testing of simufilam.
Summary of Preclinical Effects
Simufilam
Intracerebroventricular (ICV)
Aβ42 infusion
mouse model
Triple
transgenic
AD mouse
model
Post-mortem
human AD
brain tissue
Post-mortem human
age-matched control
brain tissue treated
with Aβ42 in vitro
Reduced FLNA linkage to α7nAChR/TLR4 √ √ √ √
Reduced Aβ42 bound to α7nAChR √ √ √ √
Reduced amyloid deposits and NFTs √ √
Reduced tau hyperphosphorylation √ √ √
Improved function of α7nAChR, NMDAR
and insulin receptors √ √ √ √
Improved synaptic plasticity
(activity-dependent Arc expression) √ √
Reduced inflammatory cytokine levels √ √
Improved cognition/behavior √
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Clinical Hypothesis
12
Hypothesis
Simufilam is a diseasemodifying drug for
Alzheimer’s disease that also
provides symptomatic
improvement.
Phase 2b Study Objective
Evaluate safety, biomarkers
and cognition in a randomized,
placebo-controlled study of
simufilam.
Phase 2b - Study Design
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Objective
Patient Enrollment
Mild-to-moderate Alzheimer’s,
MMSE ≥16 to 26
Key Inclusion Criterion:
CSF Total tau/Aβ42 ≥ 0.28
Sixty (64) patients recruited
across 9 study sites in the U.S.
Simufilam 50 mg oral, twice-daily
Simufilam 100 mg oral, twice-daily
Matching placebo
Double-blind, Randomized, Placebo-controlled, Multi-center, Safety Study Baseline Cognition Test
2nd CSF Draw & Cognition Test
1:1:1 Randomization
28-Day Treatment Period Day 28 Day 1
Phase 2b Results – Safety & Baseline
• Simufilam was safe and well-tolerated
• No serious adverse events
• No drug-related patient discontinuation
• No drug-related adverse events
• Common, non-persistent side-effects observed in placebo & drug groups
• Baseline characteristics were well-balanced between treatment groups,
assigned through (1:1:1) randomization.
14
Phase 2b Summary of Results - CSF Biomarkers
+p < 0.05, †p < 0.01, # p ≤ 0.001,
*p < 0.0001 vs. placebo
% Change - Baseline to Day 28
-55%
-45%
-35%
-25%
-15%
-5%
5%
15%
25%
Placebo 50 mg 100 mg
#
+
#
#
#
*
*
#
*
*
†
†
†
#
# #
# #
#
+
+
+
15
Phase 2b Results – Patient Responder Analysis
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95%
98%
98%
98%
0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100%
Biomarkers of BBB Integrity
Biomarkers of Neurodegeneration
Biomarkers of Neuroinflammation
Tau/p-Tau Biomarkers
% of Patients Who Responded to Simufilam on CSF Biomarkers
Phase 2b Study Conclusions
• Simufilam showed promising treatment effects in a double-blind, randomized,
placebo-controlled study in patients with mild-to-moderate Alzheimer’s disease.
• Simufilam improved a panel of validated biomarkers of disease pathology,
neuroinflammation and integrity of the blood-brain barrier.
• Evidence of simufilam’s safety and efficacy in Alzheimer's disease still needs to be
established by FDA statutory requirements.
• Phase 3 studies are on-going with simufilam in patients with Alzheimer’s disease.
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Ongoing Open-label Study
• We are conducting a one-year, open-label safety study of simufilam, with
scientific and financial support from the National Institutes of Health (NIH).
• Study subjects have mild-to-moderate Alzheimer’s disease (MMSE 16 to 26) and are
evaluated for safety, cognition and behavior.
• Study is fully enrolled: ≈ 200+ study subjects from 16 investigator sites in the U.S. and Canada.
• Simufilam appears safe and well-tolerated.
• In 2021, we announced top-line safety & cognitive results of the first 50 study
subjects who completed 6, 9 & 12 months of open-label treatment with simufilam
100 mg b.i.d.
• Treatment effects observed in an open-label study are not proof of drug safety or efficacy, nor can
open-label data predict clinical success in a Phase 3 program.
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Open-label Study – Cognition
Change in cognition scores observed in first 50 study subjects who completed
6, 9 & 12 months of open-label treatment with simufilam 100 mg b.i.d.
19
Mean ADAS
-Cog11
Change from Baseline
0
-1
-2
-3
-4
+3
+2
+1
6 months 9 months 12 months
-1.6
-3.0
I
M
P
R
O
V
E
D
E
C
L
I
N
E
P < 0.001 by
paired t test:
Baseline vs. 12 Months
-3.2
Expected Rate of Cognitive Decline in AD - Literature
• Cognitive decline was reported in a published,
meta-analysis of 20,000 patients with mild-tomoderate AD in randomized, controlled trials1
.
5.5 point average decline over 12 months on ADASCog among study subjects who were administered
placebo in randomized, controlled trials.
• Cognitive decline was reported in two P3
studies of Biogen’s aducanumab in patients
with early AD2
:
5.2 point average decline over 18 months on ADASCog among study subjects who were administered
placebo in randomized, controlled trials.
20
Meta-analysis Of Placebo Group Decline1
Sources:
1 Disease Progression Meta-analysis Model in Alzheimer’s disease (Ito, et al., Pfizer Global Research), Alzheimer’s & Dementia 6 (2010) 39-53
2 EMERGE and ENGAGE Topline Results (2020), https://investors.biogen.com/static-files/f91e95d9-2fce-46ce-9115-0628cfe96e83
I
M
P
R
O
V
E
D
E
C
L
I
N
E
Note: Dash lines are 90% predicted intervals.
Open-label Study - CSF Biomarkers at 6 Months (N=25)
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-80%
-70%
-60%
-50%
-40%
-30%
-20%
-10%
0%
P-tau Total tau TREM2 YKL40 Neurogranin NfL HMGB1
-18%
-38%
-65%
-44%
-55% -53%
% Change from Baseline
-72%
P < 0.00001 for all by paired t test.
Not shown: CSF Aβ42 increased significantly (+84%), as expected.
181 s
Cognition Maintenance Study (CMS)
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Goal is to compare cognition in ≈100 AD patients who continue vs. discontinue
simufilam following 1-year open-label treatment.
CMS was initiated May 2021. As of April 2022, 69 subjects have now been enrolled.
simufilam
100 mg b.i.d.
Open-label Treatment
Randomization
1:1
Continuation (simufilam 100 mg BID)
Discontinuation (placebo)
simufilam
100 mg b.i.d.
COGNITION MAINTENANCE STUDY
Double-blind, randomized, placebo-controlled Open-label Treatment
Month 0 Month 12 Month 18
Primary Endpoint
Change in ADAS-Cog, Baseline (Month 12) to Month 18
Month 24+
Regulatory Strategy
• Successful End-of-phase 2 (EOP2) meeting was held with FDA January 2021.
• EOP2 meeting objectives were to gain general agreement around a Phase 3 clinical program and
statutory requirements for a 505(b)(1) NDA submission and marketing approval of simufilam for the
treatment of mild-to-moderate Alzheimer’s disease.
• FDA agrees that the completed Phase 2 program, together with well-defined Phase 3 clinical program,
are sufficient to show evidence of clinical efficacy.
• Agreement on use of co-primary efficacy endpoints to assess treatment benefits.
• Agreement reached with FDA on two Special Protocol Assessments for Phase 3.
23
Phase 3 Program Overview
24
Co-Primary Endpoints Secondary Endpoints
Enrollment
Target
Simufilam
Treatment
Length of
Treatment Cognition Scale Function
Scale
Cognition +
Function Scale
Dementia-related
Behavior Scale
1
st Phase 3 ~ 750
Subjects 100 mg 52-weeks ADAS-Cog12 ADCS-ADL iADRS NPI12
2
nd Phase 3 ~ 1,000
Subjects
100 mg or
50 mg 76-weeks ADAS-Cog12 ADCS-ADL iADRS NPI12
Our Phase 3 program consists of two double-blind, randomized, placebo-controlled
studies in patients with mild-to-moderate Alzheimer’s disease (MMSE 16 to 27).
ADAS-Cog = The Alzheimer’s Disease Assessment Scale – Cognitive Subscale, a measure of cognition
ADCS-ADL = Alzheimer’s Disease Cooperative Study – Activities of Daily Living, a measure of health function
iADRS = integrated Alzheimer’s Disease Rating Scale, a composite measure of cognition and health function
NPI = Neuropsychiatric Inventory
Phase 3 Studies
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Over 100 clinical investigational sites are now recruiting Alzheimer's patients.
ADAS-Cog = The Alzheimer’s Disease Assessment Scale – Cognitive Subscale, a measure of cognition
ADCS-ADL = Alzheimer’s Disease Cooperative Study – Activities of Daily Living, a measure of health function
iADRS = integrated Alzheimer’s Disease Rating Scale, a composite measure of cognition and health function
NPI = Neuropsychiatric Inventory
➢ 52-week Phase 3 study, initiated Fall 2021.
➢ ≈ 750 subjects to be randomized (1:1) to simufilam
100 mg or placebo twice daily.
➢ Co-primary efficacy endpoints are ADAS-Cog12, a
cognitive scale, and ADCS-ADL, a functional scale.
➢ A secondary efficacy endpoint is iADRS, a clinical
tool that combines cognitive functional scores from
ADAS-Cog & ADCS-ADL.
➢ Other secondary endpoints include plasma
biomarkers of disease and NPI to assess dementiarelated behavior.
➢ 76-week Phase 3 study, initiated Fall 2021.
➢ ≈ 1,000 subjects to be randomized (1:1:1) to simufilam 100
mg, 50 mg or placebo twice daily.
➢ Co-primary efficacy endpoints are ADAS-Cog12, a cognitive
scale, and ADCS-ADL, a functional scale.
➢ A secondary efficacy endpoint is iADRS, a clinical tool that
combines cognitive functional scores from ADAS-Cog &
ADCS-ADL.
➢ Other secondary endpoints include CSF, plasma and
imaging biomarkers of disease and NPI to assess
dementia-related behavior.
SavaDx: Our Investigational Diagnostic for Alzheimer’s
• The underlying science for simufilam supports the
development of a diagnostic technology to detect
Alzheimer’s disease with a simple blood test, called
SavaDx. Goal is to detect Alzheimer’s disease before
the appearance of memory loss.
• SavaDx is an early-stage product candidate, benefiting
from long-term scientific & financial support from NIH.
• Lower priority program as compared to simufilam.
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• SavaDx was evaluated for its ability to detect treatment effects
of simufilam versus placebo in a Phase 2b, randomized,
controlled study in patients with Alzheimer’s. This SavaDx clinical
dataset was presented July 2021 at AAIC. Erratum: the AAIC data
and data analysis are correct, however, visual errors that were not
caught in proofing were disclosed by the Company September 2021.
Intellectual Property
• Simufilam is a novel molecule. We own exclusive, worldwide rights to simufilam
and related technologies, without financial obligations to any third party.
• Composition of matter patent protection for simufilam and other novel filaminbinding molecules includes six issued patents and currently runs through 2033.
• We do not have issued patents in the U.S. for SavaDx. In the U.S., we believe
SavaDx may be protected by trade secrets, know-how and other proprietary rights
technology.
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Financials
Eric Schoen - Chief Financial Officer
28
29
Nasdaq ticker: SAVA
Shares Outstanding ≈ 40.0 million
Financials at December 31, 2021
Cash Balance ≈ $233.4 million
Debt none
Financials
Est. Cash Use for Operations in the 1st Half of 2022 is Approximately $25 to $30 million.
Thank you!
Appendix: Key Publications
Journal of Prevention of Alzheimer’s Disease
2020; DOI: 10.14283
PTI-125 Reduces Biomarkers of Alzheimer’s Disease In Patients:
http://link.springer.com/article/10.14283/jpad.2020.6
Neuroimmunology and Neuroinflammation
2017;4:263-71:
Altered filamin A enables amyloid beta induced tau hyperphosphorylation and neuroinflammation in Alzheimer’s disease:
http://nnjournal.net/article/view/2313
Neurobiology of Aging
(Volume 55) July 2017, Pages 99—114)
PTI-125 binds and reverses an altered conformation of filamin A to reduce Alzheimer's disease pathogenesis:
http://www.neurobiologyofaging.org/article/S0197-4580(17)30087-8/
Erratum: Figure 12 contains an image showing 12 control bands; it should show 13. This visual error was not caught in proofing. The
data analysis was based on all 13 control bands. This error does not impact data conclusions.
Alzheimer's & Dementia
Volume 8, Issue 4, Supplement, 1 July 2012, Pages p259-p260
PTI-125 reduces amyloid-related Alzheimer's pathogenesis by targeting filamin A:
https://www.sciencedirect.com/science/article/pii/S1552526012008242