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April 2021

An update and baseline data from the Phase 2/3 GAIN trial of COR388 (atuzaginstat) a novel bacterial virulence factor inhibitor for the treatment of Alzheimer’s Disease

Michael Detke, MD PhD1, Shirin Kapur, PhD1, Marwan Sabbagh, MD2, Mark Ryder, DMD3, Ira Goodman, MD4, Debasish Raha, PhD1, Florian Ermini, PhD1, Mai Nguyen, PhD1, Ursula Haditsch, PhD1, Joanna Bolger1, Dave Hennings, PhD1,

Kim Perry, PhD5, Casey Lynch1, Hatice Hasturk, DDS, PhD6, Leslie J. Holsinger, PhD1, Stephen Dominy, MD1

(1) Cortexyme, South San Francisco, CA; (2) Cleveland Clinic, Las Vegas, NV; (3) UCSF, San Francisco, CA; (4) Bioclinica, Orlando, FL; (5) Innovative Analytics, Portage, MI; (6) Forsyth Forsyth Institute, Cambridge, MA

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Certain information contained in this presentation and statements made orally during this presentation relate to or are based on studies, publications, surveys and

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reliable as of the date of this presentation, it has not independently verified, and makes no representation as to the adequacy, fairness, accuracy or completeness

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Disclaimer

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Disclosures

Drs. Sabbagh, Goodman, Hasturk, Perry and Ryder are consultants for Cortexyme,

compensated for their time (no stock/options).

All other authors are full-time employees of Cortexyme and holders of Cortexyme

stock/options.

Most of the work presented here was funded by Cortexyme, Inc.

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GAIN Trial Overview and Milestones

• GAIN is a double blind, placebo-controlled, randomized 1-year study in mild - moderate AD

patients of the GingipAIN hypothesis of Alzheimer’s.

• Based on the discovery of Porphyromonas Gingivalis (Pg) in the brains AD subjects, this is a

novel mechanism, upstream of immune system activation, proteinopathy, synaptic dysfunction,

and neurodegeneration.

• Ongoing publications and data presentations continue to strengthen evidence for the gingipain

hypothesis; the GAIN trial is designed to be the key clinical test and a potentially pivotal trial.

• Randomization completed Q4 2020. Total enrollment is N=643. N=233 in periodontal REPAIR

sub-study.

• Baseline demographics and biomarkers consistent with appropriate population.

• 90% of patients have moderate-severe periodontal disease at baseline.

• 100% of patients positive for Pg IgG at baseline.

• Topline data expected in Q4 2021 for both AD & Perio.

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NeurodegenerationTau fragmentation

ApoE fragmentation

Lysosomal dysfunction

P. gingivalisinfection

Braininfiltration

Gingipain

(protease virulence factor)

secretion

Aging

Genetic risk (ApoE4,

TLR4, CR1, TREM2)

Trauma

Bacterial load

Host responseAmyloid beta production

Microglia activation

Neuroinflammation

Complement induction

Inflammasome

Bacterial Brain Infiltration Triggers Alzheimer’s Pathology

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Seminal Discovery: P. gingivalis Found in Brains of >90% of AD Patients

Source: Collaboration with University of Auckland/ Neurovalida ****p<0.0001, Dominy et al. Science Advances, 2019

Immunohistochemistry

of middle temporal

gyrus microarray

Tau load(normalized to control)

100

10

1

0.1

Age-matched

ControlsAlzheimer’s

Arg

inin

e g

ingip

ain

load

(norm

aliz

ed t

oco

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Arg

inin

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ingip

ain

load

(norm

aliz

ed t

oco

ntr

ol)

10

1

0.1

****

0.001 0.01 0.1 1 10 100 1000

Gingipain load correlates to symptoms and pathology

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Evidence of Causation: Oral Pg Infection Induces AD Pathology in Mice

*p< 0.05,**p<0.01, ***p<0.001, ****p<0.001, *****p<0.001

Source: Adapted from Ilievski, et al. Chronic oral application of a periodontal pathogen results in brain inflammation, neurodegeneration and amyloid beta production in wild type

mice PLOS: One 2018

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Tau Tangle-Like Neurons

Cont. Inf.

*****14

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P.g

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P. Gingivalis Infiltrates the

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■ CA1

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Brain pathology at 22 weeks post oral infection of wild type mouse with P. gingivalis

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Atuzaginstat Acts Upstream of Alzheimer’s Induced Pathology

Source: Cortexyme atuzaginstat (COR388) dose response study, Mean +/- SEM *p< 0.05,**p<0.01, ***p<0.001, Science Advances, 2019

Week 1 2 3 4

56 7 8 9 10

0COR388 10 or 30 mg/kg po 2x/day

3x oral P.g. / week

Infected Inf + COR388

Copy

#/

100

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0

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0.20

***

0.0

0.5

1.0

1.5

2.0

2.5

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Infected Inf + COR388

Infected Inf + COR388

Infected Inf + COR388

Efficacious in wild type mouse model for sporadic Alzheimer’s disease

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Atuzaginstat Showed Favorable Trends on Multiple Cognitive Measures

Source: Cortexyme MAD study: *p< 0.05, ***p<0.001

MM

SE

Sco

re

Days of treatment

CA

NTA

Bco

mp

osite

(Zscore

)

Days of treatment Pro

po

rtio

nP

rep

ositio

n:to

talco

nte

nt

Days of treatment

COR388 (n=6) Placebo (n=3)

28-day Phase 1b MAD study in AD patients

10

Days of treatment

%o

fb

aselin

ele

vel

*

0 10 20 30

130

120

110

baseline

90

80

70

60

days

**

%o

fb

aselin

ele

vel

Atuzaginstat Target Engagement of Key Endpoints

Source: Cortexyme ApoE and MAD study: *p< 0.05, ** p< 0.01

Placebo (n=2)COR388 (n=4)

0 28

Placebo (n=2)COR388 (n=6)

28-day Phase 1b MAD study in AD patients

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Pivotal P2/3 GAIN Trial Design: Atuzaginstat in Alzheimer’s Disease

• Mild to Moderate: MMSE

12-24

• Ages 55-80

• Stable symptomatic

therapies allowed

• Target N=573

RandomizationScreening

Co-Primary:

ADAS-Cog11 and ADCS-ADL

Secondary:

CDR-SB, MMSE and NPI

Exploratory:

Winterlight, MRI (hippocampal

volume and cortical thickness)

Biomarkers of Pg and

gingipain activity: blood, saliva

Biomarkers of Alzheimer’s:

CSF Aβ, tau, p-tau

Markers of disease

modification: MRI volumetric

measures

Endpoints

Key Eligibility Criteria

• Enrollment initiated Apr. 2019; completed Sept. 2020

• Interim analysis in December 2020 successfully

completed with no sample size adjustment

• Top-line data expected on time Q4 2021

• 233 subjects

• Assessment of pocket depth

and clinical attachment level at

6 and 12 months

Timelines Periodontal REPAIR sub-study

Placebo

Low dose (40 mg BID)

48-week Treatment Period

(Total N=643)

More information: www.gaintrial.com

High dose (80 mg BID)

6-week Safety Follow-up

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GAIN Baseline Demo: Population and Stratification as Expected

Parameter Overall (N=643)

Age at Informed Consent (years) 69.1 (55 – 80)

Sex

Male 278 (43%)

Female 365 (57%)

Race and Ethnicity

Black or African American 42 (7%)

White, Hispanic or Latino 68 (11%)

White, Not Hispanic/Latino 505 (79%)

Other 10 (2%)

Missing 18 (3%)

Parameter Overall (N=643)

Region

North America 447 (70%)

Europe 196 (30%)

MMSE, n (%)

Moderate >=12 to <=18 324 (50%)

Mild >=19 to <=24 319 (50%)

ApoE4 (Stratum), n (%)

ApoE4 Positive 414 (64%)

non-ApoE4 229 (36%)

Cholinesterase Inhibitor/Memantine Use

Yes 476 (74%)

No 167 (26%)

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Biomarker Highlights: Baseline CSF Ab 42/40, Tau and P-Tau

Approximately 84% of GAIN subjects have CSF markers characteristic of Alzheimer’s Disease diagnosis

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Over 90% of GAIN Subjects in the Periodontal REPAIR

Sub-Study Have Moderate to Severe Periodontal Disease at Baseline

Diagnosis based on Pocket depth and Clinical attachment loss measures (N=233)

0

1 0

2 0

3 0

4 0

5 0

6 0

7 0

8 0

9 0

1 0 0

% o

f s

ub

jec

ts

N o n e -

M i l d

M o d e r a t e -

S e v e r e

0

4

8

1 2

1 6

2 0

2 4

2 8

3 2

Nu

mb

er

of t

ee

th

N o n e -

M i l d

M o d e r a t e -

S e v e r e

Diagnosis based on PD and CAL Number of teeth

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100% of subjects analyzed have P. gingivalis specific IgG

in plasma at baseline indicating systemic infection

100% of GAIN subjects have

evidence of systemic P. gingivalis

exposure and 78% have IgG

antibody titers that correlate with

periodontal disease. N=638.

Offenbacher et al, J Periodontology 2007 Oct; 78(10):1911-25

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Summary

• Data continue to accumulate supporting the gingipain hypothesis of Alzheimer’s, periodontal

disease and other degenerative disorders

• The GAIN trial, designed to be a key clinical proof of concept and potentially pivotal trial, is

fully enrolled

• Baseline data* support that this is an appropriate population for testing atuzaginstat for AD

• Demographics

• Aβ, Total tau and p-Tau 181 in CSF

• Pg antibodies in serum

• Periodontal disease data in a sub study

• Topline data will be reported by Q4 2021

• Alzheimer’s Disease

• Periodontal Disease

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Acknowledgements

Cortexyme team

Stephen Dominy, MDCasey Lynch, MSLeslie Holsinger, PhDDave Hennings, PhDJoanna BolgerShirin Arastu-Kapur, PhDMai Nguyen, PhDDebashish Raha, PhDFlorian Ermini, PhD Ursula Haditsch, PhDSean BroceTheresa Roth

Clinical Investigators in Phase 1 & Clinical Advisors

Merce Boada, MD, PhDMark Brody, MDJeffrey Cummings, MDMartin Farlow, MDIra Goodman, MDHatice Hasturk, DDS, PhDClive Holmes, PhDLouis Kirby, MDThomas Laughren, MDDavid Munoz, MDMark Ryder, DMD

Marwan Sabbagh, MDPhilip Scheltens, MD, PhDLon Schneider, MD, MSEric Siemers, MDMarwan Sabbagh, MDPierre Tariot, MDStephen Thien, MD

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THANK YOU