COR388, A NOVEL GINGIPAIN INHIBITOR, DECREASES FRAGMENTATION OF APOE - - PowerPoint PPT Presentation

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

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

• therwise. 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

• pportunity will meet your investment objectives, or that you will receive a return of all or part of such investment. Investment results may vary significantly
• ver 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.

Neurodegeneration

Tau fragmentation ApoE fragmentation Lysosomal dysfunction

Host response P . gingivalis infection Brain infiltration Gingipain secretion

Aging Genetic risk (ApoE4, TLR4, CR1, TREM2) Trauma Bacterial load Amyloid beta production Microglia activation Neuroinflammation Complement induction Inflammasome

4

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

P . gingivalis gingipains in the brain of Alzheimer’s patients correlates 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

Relative TNF alpha gene expression Neuroinflammation 2.5 2 1.5 1 0.5

• P. gingivalis 16S

RNA copies / 5 FFPE x10 10 8 6 4 2

• P. Gingivalis Infiltrates the Brain

Amyloid beta Plaques / field 1 2 3 4 5 6 Amyloid Beta Plaques # pTau / field 14 8 6 4 2 10 12 Tau Tangle-Like Neurons Microglia / field 14 8 6 4 2 10 12 Activated Microglia % Intact neurons / field 80 60 40 20 100

CA1 DG

Neurodegeneration

Evidence of causation Oral Pg infection 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

2,000 4,000 6,000

Infected COR388

Copy # / 100 ng DNA

***

0.00 0.05 0.10 0.15 0.20 Infected COR388 pg / mg Protein

***

0.0 0.5 1.0 1.5 2.0 2.5

Infected COR388

pg / mg Protein

**

2,000 4,000 6,000 8,000 10,000

Infected COR388

Interneurons / mm3

*

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: RgpB Green: 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 ApoE fragments Full length ApoE

11

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

37kDa 20kDa 15kDa

ApoE fragments + ApoE3 + ApoE4 Full length ApoE Source: Cortexyme studies

Putative Gingipain Cleavage Sites Lie Within Important Functional Domains

Receptor Binding Lipid Binding

Receptor Binding aa140-150: LDLR binding aa139-152: C1q binding

COOH Lipid Binding Receptor Binding NH2 Hinge

ApoE2 ApoE3

COOH NH2 COOH NH2

ApoE4

112 158

Cys Cys Cys Arg Arg Arg

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

Hinge Region

Source: Cortexyme studies

Source: Cortexyme studies 13

Gingipains fragment ApoE and preferentially ApoE4

100 200 300 400 500 600 700 E3 0 min E3 1 min E4 0 min E4 1min 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 # peptides detected by mass spec

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) Control Infection Infection + COR388 Infection + COR613 Infection + COR388/613 COR388/613

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 are reduced in Phase 1b COR388-dosed subjects Low MW ApoE fragments 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 MMSE Score CANTAB composite (Z score) Proportion Preposition: total content 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 2021

Image 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 team Stephen Dominy, MD Casey Lynch, MS Leslie Holsinger, PhD Dave Hennings, PhD Shirin Arastu-Kapur, PhD Mai Nguyen, PhD Debashish Raha, PhD Florian Ermini, PhD Ursula Haditsch, PhD Sean Broce Theresa Roth

20

Clinical investigators Phase 1a/b and advisors Mark Brody, MD Jeffrey Cummings, MD Martin Farlow, MD Ira Goodman, MD Louis Kirby, MD David Munoz, MD Mark Ryder, DMD Marwan Sabbagh, MD Lon Schneider, MD, MS Eric Siemers, MD Marwan Sabbagh, MD Pierre Tariot, MD Stephen Thien, MD

Acknowledgements

THANK YOU