COR388, A NOVEL GINGIPAIN INHIBITOR, DECREASES FRAGMENTATION OF APOE IN ALZHEIMER’S DISEASE CENTRAL NERVOUS SYSTEM

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NeurodegenerationTau fragmentation

ApoE fragmentationLysosomal dysfunction

Host response

P. gingivalisinfection

Brain infiltration

Gingipain secretion

AgingGenetic risk (ApoE4, TLR4, CR1, TREM2)

TraumaBacterial load

Amyloid beta productionMicroglia activationNeuroinflammation

Complement inductionInflammasome

4

P. gingivalis has been discovered in AD brain and triggerspathology and immune system activation

P. gingivalis gingipains in the brain of Alzheimer’s patientscorrelates to pathology

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

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

Rel

ativ

e T

NF

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Neuroinflammation

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1.51

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ging

ival

is16

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cop

ies /

5 F

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P. Gingivalis Infiltrates the Brain

Am

yloi

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Amyloid Beta Plaques

# pT

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8642

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Tau Tangle-Like Neurons

Mic

rogl

ia /

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Activated Microglia

% In

tact

ne

uron

s / fi

eld

0

80604020

100

CA1DG

Neurodegeneration

Evidence of causation

Oral Pginfection of WT mouse induces AD pathology after 22 weeks

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

Gingipain inhibitor COR388 acts upstream of infection-induced AD pathology in wild-type mice

Source: Dominy et al, 2019; Mean +/- SEM *p< 0.05,**p<0.01, ***p<0.001

0

2,000

4,000

6,000

InfectedCOR388

Cop

y #

/ 100

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***0.00

0.05

0.10

0.15

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InfectedCOR388

pg /

mg

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***

0.0

0.5

1.0

1.5

2.0

2.5

InfectedCOR388

pg /

mg

Prot

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2,000

4,000

6,000

8,000

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InfectedCOR388

Inte

rneu

rons

/ m

m3

*

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

5 weeks 10 weeks

Inf +Inf +Inf +Inf +

COR388, gingipain inhibitor currently in Phase 2/3 clinical development

• Novel & proprietary small molecule inhibitor• Potent: Kgp IC50 < 50pM• Selective over 800 human anti-targets• Orally bioavailable, brain penetrant• Large therapeutic window in safety studies• Well tolerated in Phase 1 a/b clinical studies• Composition of matter granted until 2035

with additional patents pending

Human brain Co-IHC: Gingipains are present in AD neurons and astrocytes, a primary source of ApoE in the brain

merge control merged

Red: RgpBGreen: GFAP (glia/astrocytes)Yellow: MAP2 (neurons)

Source: Huang et al 2001 (Gladstone), Mouchard et al 2019, Western blot: Cortexyme studies 10

ApoE fragments are found in AD brain

Low MW ApoEfragments

Full length ApoE

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ApoE is cleaved by P. gingivalis infected cells, ApoE4 > ApoE3

37kDa

20kDa

15kDaApoEfragments

+ ApoE3 + ApoE4

Full length ApoE

Source: Cortexyme studies

Putative Gingipain Cleavage Sites Lie Within Important Functional Domains

Receptor Binding

LipidBinding

Receptor Bindingaa140-150: LDLR bindingaa139-152: C1q binding

COOH

LipidBinding

ReceptorBinding

NH2

Hinge

ApoE2

ApoE3 COOHNH2

COOHNH2ApoE4

112 158Cys Cys

Cys Arg

Arg Arg

aa136** = Christchurch mutation, resulting in R to S change

HingeRegion

Source: Cortexyme studies

Source: Cortexyme studies

13

Gingipains fragment ApoE and preferentially ApoE4

0

100

200

300

400

500

600

700

E30 min

E31 min

E40 min

E41min

Mass Spec detection of peptides produced from gingipain (Kgp+RgpB) digestion of ApoE3 and ApoE4

Undigested (0 min) and digested (1 minute)

Each color represents unique peptides produced

# pe

ptid

es d

etec

ted

by m

ass s

pec

Source: Cortexyme studies 14

Full length endogenous ApoE is reduced in infected astrocytes, effect is blocked by COR388, gingipain inhibition

APOE

GAPDH

Human iPSC-derived astrocytes (APOE3/4 genotype) Co

ntro

l

Infe

ctio

n

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COR3

88

Infe

ctio

n +

COR6

13

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COR3

88/6

13

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13

ApoE fragmentation by gingipains will affect synapses and complement regulation

ApoE is important for synaptic maintenence

ApoE is important for regulation of C1q classical complement pathway

adapted from Yin et al, Nature Med. 2019 Mar;25(3):496-506

adapted from Barres and Smith, Science 2001, Nov;(294)5545:1296-1297

ApoE fragments are found in AD patient CSF and can be reduced by COR388 treatment

ApoE fragments found in AD CSF

CSF ApoE fragments arereduced in Phase 1b

COR388-dosed subjects

Low MW ApoEfragments

Source: Cortexyme studies

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

Source: Cortexyme Phase 1b study: *p< 0.05, ***p<0.001

Days of treatment Days of treatment Days of treatment

MM

SE S

core

CAN

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sco

re)

Prop

ortio

n Pr

epos

ition

: tot

al c

onte

nt

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

Phase 2/3 GAIN Trial

Mild-to-moderate AD

US and EU

Approximately 90 sites in US and EU

570 patients

Topline results Q4 2021Image Subtitle

18

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Conclusions

• P. gingivalis infection– Present in the brains of AD patients– Infection in wild-type mouse model recreates the pathology seen in AD

• Gingipain proteases from P. gingivalis– Correlate with tau and ubiquitin pathology– Cleave ApoE (ApoE4 > ApoE3)

• COR388, a small-molecule inhibitor of lysine-gingipain– Blocked or reversed AD pathology seen in the mouse model– Blocks pathological ApoE cleavage– Decreased ApoE fragments in the CSF of AD patients in Phase 1b

• COR388 was well-tolerated in Phase 1a/b; Phase 2/3 GAIN trial is underway

Cortexyme teamStephen Dominy, MDCasey Lynch, MSLeslie Holsinger, PhDDave Hennings, PhDShirin Arastu-Kapur, PhDMai Nguyen, PhDDebashish Raha, PhDFlorian Ermini, PhD Ursula Haditsch, PhDSean BroceTheresa Roth

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Clinical investigators Phase 1a/b and advisorsMark Brody, MDJeffrey Cummings, MDMartin Farlow, MDIra Goodman, MDLouis Kirby, MDDavid Munoz, MDMark Ryder, DMDMarwan Sabbagh, MDLon Schneider, MD, MSEric Siemers, MDMarwan Sabbagh, MDPierre Tariot, MDStephen Thien, MD

Acknowledgements

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