cor388, a novel gingipain inhibitor, decreases ......certain information contained in this...
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COR388, A NOVEL GINGIPAIN INHIBITOR, DECREASES FRAGMENTATION OF APOE IN ALZHEIMER’S DISEASE CENTRAL NERVOUS SYSTEM
Disclaimer
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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
alph
a ge
ne e
xpre
ssio
n
Neuroinflammation
2.52
1.51
0.50P.
ging
ival
is16
SR
NA
cop
ies /
5 F
FPE
x1010
86420
P. Gingivalis Infiltrates the Brain
Am
yloi
d be
ta
Plaq
ues /
fiel
d
0123456
Amyloid Beta Plaques
# pT
au/ f
ield
0
14
8642
1012
Tau Tangle-Like Neurons
Mic
rogl
ia /
field
0
14
8642
1012
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
ng
DN
A
***0.00
0.05
0.10
0.15
0.20
InfectedCOR388
pg /
mg
Prot
ein
***
0.0
0.5
1.0
1.5
2.0
2.5
InfectedCOR388
pg /
mg
Prot
ein **
0
2,000
4,000
6,000
8,000
10,000
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
11
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
Infe
ctio
n +
COR3
88
Infe
ctio
n +
COR6
13
Infe
ctio
n +
COR3
88/6
13
COR3
88/6
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
TAB
com
posi
te (Z
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
19
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
20
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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