Cortexyme : Corporate Overview January 2020

January 26, 2021

Disclaimer

Certain information contained in this presentation and statements made orally during this presentation relate to or are based on studies, publications, surveys and other data obtained from third-party sources and Cortexyme's own internal estimates and research. While Cortexyme believes these third-party sources to be 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 of, any information obtained from third-party sources. While Cortexyme believes its internal research is reliable, such research has not been verified by any independent source. This presentation contains information that is highly confidential and/or privileged. The information is intended only for the use of individuals or entities to which it is addressed. If you are not the intended recipient, you are hereby notified that any reliance, disclosure, copying, distribution, or taking of any action on the contents of this material is strictly prohibited. This presentation contains forward-looking statements. Forward-looking statements are neither historical facts nor assurances of future performance. Instead, they are based on Cortexyme's current beliefs, expectations and assumptions regarding the future of its business, its future plans and strategies, its clinical results and other future conditions. All statements other than statements of historical facts contained in this presentation, including statements regarding future results of operations and financial position, business strategy, current and prospective markets or products, clinical activities, regulatory approvals, degree of market acceptance, and plans and objectives of management for future operations, are forward- looking statements. The words "may," "will," "should," "expect," "plan," "anticipate," "could," "intend," "target," "project," "estimate," "believe," "predict," "potential" or "continue" or the negative of these terms or other similar expressions are intended to identify forward-looking statements, although not all forward- looking statements contain these identifying words. The forward-looking statements in this presentation represent Cortexyme' views as of the date of this presentation. Although Cortexyme believes the expectations reflected in such forward-looking statements are reasonable, it can give no assurance that such expectations will prove to be correct. Accordingly, readers are cautioned not to place undue reliance on these forward-looking statements. Except as required by applicable law, Cortexyme do not plan to publicly update or revise any forward-looking statements contains herein, whether as a result of any new information, future events, changed circumstances or otherwise. No representations or warranties (expressed or implied) are made about the accuracy of any such forward- looking statements. New risk factors and uncertainties may emerge from time to time, and it is not possible to predict all risk factors and uncertainties. There can be no assurance that the opportunity will meet your investment objectives, or that you will receive a return of all or part of such investment. Investment results may vary significantly over any given time period. The appropriateness of a particular investment or strategy will depend on an investor's individual circumstances and objectives. We recommend that investors independently evaluate specific investments and strategies.

Corporate update and upcoming milestones

• Topline data from 643 subject pivotal efficacy study in Alzheimer's disease Q4 2021, 90% rollover of eligible participants to open label extension to date
• Topline data from 233 subject periodontal disease Phase 2 study Q4 2021
• New Phase 2 PEAK trial in Parkinson's disease, initiating start up activities Q1 2021
• Proprietary small molecules with MOA upstream of neurodegeneration, inflammation and other pathology
• Expanding evidence base includes human, animal causation and clinical studies
• Q4 2020 proforma cash, equivalents and investments: $184.3 million

5.8M

People in the US with Alzheimer's

$ 325B

Economic burden

Alzheimer's Association

Pipeline Update

Evidence shows that bacterial brain infiltration triggers Alzheimer's pathology in physiological models

		Brain	Neurodegeneration
		Tau fragmentation
		infiltration	Lysosomal dysfunction
P. gingivalis			ApoE fragmentation
infection	Aging	Gingipain	Host response
	Genetic risk (ApoE4,	(protease virulence factor)	Amyloid beta production
	TLR4, CR1, TREM2)	secretion	Microglia activation
	Trauma	Neuroinflammation
	Bacterial load		Complement induction
			Inflammasome

5

Evidence base for the gingipain hypothesis

Clinical Studies

Support role of Pg in AD

MOA studies link Pg to characteristic

AD pathology

				Discovery of Pg in
				human brain
				Abeta established
	Abeta42
			as an antimicrobial
	discovered as an
			peptide
	antimicrobial
	peptide
	Epidemiological
				studies
Epidemiological
	demonstrate perio
Studies demonstrate
	is a risk factor for
perio is a risk factor for
	AD
	AD

2007

Mouse studies

show Pg causes

AD path and neurodegen

Replication of

findings of Pg in

human brain

Abeta established as an antimicrobial peptide

Epidemiological

studies

demonstrate perio is a risk factor for

AD

Expansion of animal studies showing Pg causes AD pathology

Pg in human brain

MTG

Abeta and synuclein

established as

antimicrobial

peptides

Epidemiological

studies

demonstrate perio is a risk factor for AD

Expansion of animal studies showing Pg causes AD & PD pathology

Pg in human brain

MTG and SN

Abeta and synuclein

established as

antimicrobial

peptides

Epidemiological

studies

demonstrate perio is a risk factor for AD

Today

P. gingivalis discovered in the brain of more than 90% of Alzheimer's patients, gingipain load correlates to pathology

Arginine gingipain load (normalized to control)

****

Controls Alzheimer's

Arginine gingipain load (normalized to control)

****

Tau load

(normalized to control)

Immunohistochemistry of middle temporal gyrus microarray

Source: Collaboration with University of Auckland/ Neurovalida study ****p<0.0001

Evidence of causation

Oral Pg infection of WT mouse induces AD pathology after 22 weeks

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

P. Gingivalis Infiltrates the Brain

x10

16S	FFPE	10
8
		copiesRNA/ 5
gingivalisP.	6
4
				2
				0
		Activated Microglia
			14
	field/
	10
			12
	Microglia		8
		6
				4
				2
				0

	Neuroinflammation
alphaTNFRelative	expressiongene	2.5
2
		1.5
		1
		0.5
		0

Tau Tangle-Like Neurons

	14
field/	12
8
	10
pTau#	6
2
	4
	0

Amyloid Beta Plaques

beta field	6
5
Amyloid Plaques/	4
3
	2

1

0

Neurodegeneration

100

80

Intact%	neuronsfield/	60
40

20

0

CA1

DG

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

Atuzaginstat (COR388) First in class lysine gingipain inhibitor

Small molecule optimized from proprietary library

• Potent: Target IC50 < 50pM
• Virulence factor (protease) inhibitor selectively blocks toxicity and reduces bacterial load
• Selective over 800 human anti-targets
• Orally available, brain penetrant
• Novel & proprietary small molecule
• Low COGS manufacturing
• 2 composition of matter patents granted with protection until at least 2037

Atuzaginstat acts upstream of infection induced Alzheimer's pathology in wild type mouse

Copy # / 100 ng DNA

6,000

4,000

2,000

0

***

pg / mg Protein

2.5

2.0

1.5

1.0

0.5

0.0

**

pg / mg Protein

0.20

0.15

0.10

0.05

0.00

***

Interneurons / mm3

10,000*

8,000

6,000

4,000

2,000

0

Infected

COR388 + Inf

Infected	COR388
	+
Inf

Infected	COR388
+
Inf

Infected	COR388
+
Inf

3x oral P.g. / week COR388 10 or 30 mg/kg po 2x/day

5 weeks

10 weeks

Source: Cortexyme COR388 dose response study, Mean +/- SEM *p< 0.05,**p<0.01, ***p<0.001

Phase Ib: COR388 well tolerated in older and AD patients

Drug Related Treatment Emergent Adverse Events

Cohorts 1-3: Older Healthy Volunteers; Treatment duration = 10 days

Dose	Placebo	25 mg	50 mg	100 mg
Subjects dosed	N=6	N=6	N=6	N=6
Dizziness1	0	0	1 (17%)	1 (17%)
Dysgeusia1	1 (17%)	0	0	0
Nausea1	0	0	0	1 (17%)
Presyncope2	1 (17%)	0	0	0
Restlessness1	0	0	0	1 (17%)
Tachycardia1, 3	0	0	1 (17%)	0
Cohorts 4: Patients with AD; Treatment duration = 28 days
Dose	Placebo		50 mg
Subjects dosed	N=3		N=6
Bradycardia1	1 (33%)		0
Orthostasis1	1 (33%)		0
Liver enzyme elevation2	0		1 (17%)
Pancreatic enzyme elevation1	0		1 (17%)
Transient QT Prolongation1	1 (33%)		1 (17%)
Subjects with drug related TEAE	4 (44%)	0 (0%)	4 (33%)	2 (33%)

• Mild AE severity, 2 Moderate AE severity. 3 AE consisted of 6 beats of SVT that occurred again 72 hours after stopping study drug.

Note: No Serious Adverse Events were reported

Pathological ApoE fragments reduced by COR388 in CSF 28 day study in AD patients

	130
level	120
110			baselineof level
of%baseline	70
	baseline			**
	90
	80
	60			%
	10	20	30
	0
			days
	COR388 (n=4)	Placebo (n=2)

*

Days of treatment

COR388 (n=6)

Placebo (n=2)

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

Trends to benefit on exploratory cognitive measures: MMSE, Cambridge Cognition CANTAB, and Winterlight

MMSE Score

Days of treatment

CANTAB composite (Z score)
Days of treatment
	COR388 (n=6)		Placebo (n=3)

Proportion Preposition: total content

Days of treatment

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

Pivotal GAIN trial of atuzaginstat (COR388) in

Design	Randomized, double blind, placebo controlled, parallel groups
Sample Size	643 subjects enrolled,
Placebo, low dose (40 mg BID), high dose (80 mg BID)
Treatment Period	48 weeks treatment, 6 week safety follow-up,
Open Label Extension in US
90% of eligible subjects to date have rolled into OLE
Inclusion criteria	Mild to Moderate: MMSE 12-24
Age 55-80, stable symptomatic therapies allowed
Biomarkers	Markers of Pg and gingipain activity: CSF, Blood, Saliva
Markers of Alzheimer's: CSF abeta, tau, p-tau
Interim analysis	Successfully completed when 300 patients reached 6 months of treatment, no sample
size adjustment recommended
Co-primary endpoint	ADAS-Cog11 and ADCS-ADL
Secondary endpoints	CDR-SB
MMSE
	NPI
Exploratory endpoints	Winterlight Analysis
MRI (hippocampal volume and cortical thickness)
Periodontal Efficacy Substudy	Periodontal measures: Pocket depth (PD) and clinical attachment level (CAL)

Baseline Demographics: Population and stratification as expected

Parameter	Overall (N=615*)				Parameter	Overall (N=615)
Age at Informed Consent (years)	69.0 (55 - 80)
			Region
								North America	430 (70%)
Sex
							Europe	185 (30%)
Male	267 (43%)
				MMSE, n (%)
								Moderate >=12 to <=18	314 (51%)
Female	348 (57%)
					Mild >=19 to <=24	301 (49%)
Race and Ethnicity							ApoE4 (Stratum), n (%)
Black or African American	41	(7%)						ApoE4 Positive	399 (65%)
Hispanic or Latino	75	(12%)						non-ApoE4	216 (35%)
White, Not Hispanic/Latino	472 (77%)					Cholinesterase	Inhibitor/Memantine Use
								Yes	432 (70%)
Other	10	(2%)
Missing	17	(3%)						No	183 (30%)

*Demographics of first 615 of 643 subjects prior to CTAD deadline, data not final

All subjects in GAIN trial analyzed to date have P. gingivalis specific IgG in serum at baseline indicating systemic infection

Elisa Units

100000

10000

1000

100

10

Baseline (N=250)

• 72% of subjects >119 EU, titers associated with more severe periodontal disease*
• 97% of thesubjects >54 EU titers associated with at least mild periodontal disease*

*Cutoffs from Noble et al, 2009

Interim data, not final or QC'd

>90% of GAIN trial subjects in the periodontal sub-study to date have moderate to severe periodontal disease at baseline

Diagnosis based on Pocket depth and Clinical attachment loss measures (N=228)

Interim data, not final or QC'd

Periodontal disease

Periodontal disease program overview

• GAIN trial includes 233 subjects enrolled in placebo controlled periodontal study
• Efficacy endpoints at 6 months and 1 year: Pocket Depth (PD) and clinical attachment level (CAL) expected in Q4 2021

gingipains

P gingivalis

65M

People in the US with periodontal disease

> $ 2B

Estimated

annual revenue

opportunity

Atuzaginstat shows efficacy in treating naturally occurring periodontal disease in aged dogs

COR388 reduces gingival pocket depth

Change in pocket depth score (mm) (all teeth > 3)

7
6	Vehicle

5

0.5 mg/kg COR388

4

3

2

worsening

1

n o c h a n g e p o c k e t s

0

• 1
• 2
• 3

improvement

	1 4 0		Vehicle
change
1 2 0		0.5 mg/kg COR388
pocket depth	1 0 0
8 0					*
Average	6 0
0	2 0	4 0	6 0	8 0	1 0 0
				days

Kapur et al. Pharmacology Research and Perspectives

Parkinson's disease

Reference links at www.cortexyme.com/science

Overview of Parkinson's rationale

• Current treatments: symptomatic drugs that prolong dopaminergic signaling, major unmet need for disease modification based on treatment of cause of disease
• The famous pathologist, Braak originally postulated that Parkinson's pathology begins when a neurotrophic pathogen enters the body via the gastric pathway spreading trans- synaptically from one vulnerable brain region to the next.Braak et al. 2003
• Periodontal disease is a risk factor for Parkinson's disease
• • Chen et al.Periodontal inflammatory disease is associated with the risk of Parkinson's disease: apopulation-basedretrospectivematched-cohortstudy
  • Woo et al.Associationof Tooth Loss withNew-OnsetParkinson's Disease: A NationwidePopulation-BasedCohort Study
  • Chen et al.Dental Scaling Decreases the Risk of Parkinson's Disease: A Nationwide Population- Based NestedCase-ControlStudy
  • Kaur et al.Parkinson's and periodontal disease - the missing link?
• Human data supports presence of gingipains in PD and in relevant brain areas
• Animal data supports Pg ability to trigger alpha synuclein and neurodegeneration in the SN in at risk populations

From: Olsen et al.Is P. gingivalis involved in Parkinson's disease?

AD and PD pathology spread through brain and often include mixed pathology

Braak staging in Alzheimer's disease

Source: Goedert, 2015

Lewy bodies in Alzheimer's disease: a neuropathological review of 145 cases using alpha-synuclein IHC. 2000

Synuclein-positive structures in cases with sporadic Alzheimer's disease: morphology and its relationship to tau aggregation. 2001

Lewy body pathology in familial Alzhiemer's disease: evidence for diseae and mutation-specific pathologic phenotype. 2006

Association of cerebrospinal fluid alpha synuclein and total and phospho-tau 191 and amyloid load. 2018

The relevance of cerebrospinal fluid alpha-synuclein levels to sporadic and familial AD. 2018

Alpha-synuclein, like Abeta42, behaves like an antimicrobial peptide (AMP)

Interaction of positively charged alpha syn with negatively charged bacterial membranes similar to other AMPS

Additional publications:

Gastrointestinal immunity and Alpha- synuclein

Holocranohistochemistry enables the visualization of alpha-synucleai expression in the murine olfactory system and discovery of its systemic antimicrobial effects

Alpha-synuclein Pathology and the role of the microbiota in Parkinson's disease

Amyloid-β peptide protects against microbial infection in mouse and worm models of Alzheimer's disease

Alzheimer's Amyloid-b is an antimicrobial peptide: a review of the evidence

The Alzheimer's Disease-Associated

Amyloid β-Protein Is an Antimicrobial

Peptide

Source: Park et al. Functional characterization of Alpha-synuclein protein with antimicrobial activity. Biochemical and Biophysical Research Communications 2016

Gingipains found in the substantia nigra of AD and PD patients

Preabsorption control		Massive loss of host neurons in SN in
	symptomatic Parkinson's patients
showing melanin containing	Lysine gingipain IHC	and background of melanin
dopaminergic neurons		makes quantitative comparison difficult

Source: University of Auckland/Neurovalida, Dec 2020, similar results with anti-Rgp antibody

Gingipain found to be elevated in blood of PD patients

Arginine Gingipain increased in blood of Parkinson's patients

Source: Adams et al. Parkinson's Disease: A Systemic Inflammatory Disease Accompanied by Bacterial Inflammagens. 2019

Oral Pg infection of LRRK2 mutant mice results in alpha synuclein production and degeneration of the substantia nigra

Increased Alpha synuclein in the colon (red)

- Pg

+ Pg

Neurodegeneration in the substantia nigra

MAP2

TH1 +

- Pg

+ Pg

- Pg

+ Pg

Similar effects of alpha syn. production, neurodegeneration in the SN, and inflammation seen after oral infection of in wild type mice, Renn et al. 2020

Inflammatory marker RANTES/CCL5 is induced by Pg and correlates to severity of Parkinson's in human subjects

Multiple strains of Pg associated with	RANTES correlates with severity of Parkinson's disease
human infection induce RANTES
by endothelial cells in 24 hrs

Pg strains

Rodriques et al. Porphyromonas gingivalis Strain Specific Interactions with Human Coronary Artery Endothelial Cells: A Comparative Study

Tang et al. Correlation between Serum RANTES and Severity of Parkinson's disease

RANTES significantly reduced in Cortexyme's 28 day Phase Ib human study in Alzheimer's disease

• RANTES (regulated on activation, normal T- cell expressed and secreted), a chemokine known to drive infiltration of T-cells
• Serum RANTES levels correlate with severity of Parkinson's disease (Tang 2014)
• RANTES (-28C>G) polymorphism identified as a risk factor for PD (Sahin-Calapoglu 2016)

% of day 1 level of Rantes/CCL5

1 2 0

1 0 0

• 0
  6 0
  4 0
  2 0
  0

* *

PlaceboCOR388

Atuzaginstat (COR388) 50 mg taken orally twice daily for for 28 days significantly reduced plasma levels of RANTES (CCL5) compared to placebo in AD patients. ***P< 0.001, ** P< 0.01, *P< 0.05.

Design of Phase 2 "PEAK Trial" in Parkinson's disease

• Placebo vs. atuzaginstat
• 50 subjects/arm
• Treatment duration of approximately 1 year
• Inclusion
• • Early PD
  • Age 50-85
• Endpoints
• • Digital motor endpoint
  • UPDRS
  • GI symptoms
  • Target engagement biomarkers: RANTES, Pg DNA and IgG

Upcoming milestones

Q3 Timing		Indication		Milestone
			Atuzaginstat (COR388) - Lysine gingipain inhibitor
Q4 2020	✓	Alzheimer's disease		Enrollment Complete (GAIN Trial)
Nov 2020 ✓	Alzheimer's disease		CTAD presentation: GAIN Biomarkers & Baseline Characteristics
Dec 2020 ✓	Alzheimer's disease		Interim Analysis (GAIN Trial)
Q1 2021	✓	Parkinson's disease		Study startup activities (PEAK Trial)
Q3 2021		Parkinson's disease		First patient in (PEAK Trial)
Q4 2021		Alzheimer's disease		Last Patient Last Visit (GAIN Trial)
Q4 2021		Alzheimer's disease		Top Line Data (GAIN Trial)
Q4 2021		Periodontal disease		Top line Data (GAIN trial) Phase II substudy in Periodontal disease
				COR588 - Lysine gingipain inhibitor
Q3 2020	✓	Periodontal disease		Candidate Selection/Advancement to IND enabling studies
Q2 2021		Periodontal disease		IND Enabling Studies Complete
Q3 2021		Periodontal disease		Phase I a/b initiation
				COR788/COR882 - Arginine gingipain inhibitor
Q1 2021✓		Potential in AD, Parkinson's, Perio,		Selection of arginine gingipain inhibitor leads (COR787/788)
	Cancer and other indications
Q2-Q3 2021	Potential in AD, Parkinson's, Perio		Candidate selection and initiation of IND enabling studies
Cancer and other indications

Overview

• Topline potentially pivotal Alzheimer's disease data in Q4 2021
• To date, 90% rollover of eligible participants to open label extension
• Topline efficacy data in periodontal substudy Q4 2021
• New PEAK trial in Parkinson's disease study start up 2021, first patient in anticipated Q3 2021

• MOA upstream of neurodegeneration and other pathology
• Preclinical and clinical data supports MOA
• Additional indications and compounds in preclinical development
• Q4 2020 proforma cash, equivalents and investments: $184.3 million

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