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

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P . gingivalis has been discovered in AD brain and triggers pathology and immune system activation Neurodegeneration Brain Tau fragmentation infiltration ApoE fragmentation Lysosomal dysfunction P . gingivalis infection Gingipain Host response Aging secretion Genetic risk (ApoE4, Amyloid beta production TLR4, CR1, TREM2) Microglia activation Trauma Neuroinflammation Bacterial load Complement induction Inflammasome 4

P . gingivalis gingipains in the brain of Alzheimer’s patients correlates to pathology Source: Collaboration with University of Auckland/ Neurovalida study ****p<0.0001

Evidence of causation P. Gingivalis Infiltrates the Brain Neuroinflammation Amyloid Beta Plaques x10 10 2.5 6 Relative TNF alpha RNA copies / 5 FFPE gene expression Amyloid beta P. gingivalis 16S Plaques / field 5 8 2 Oral Pg 4 6 1.5 3 4 1 infection of WT 2 2 0.5 1 mouse induces 0 0 0 AD pathology Activated Microglia Tau Tangle-Like Neurons Neurodegeneration after 22 weeks 14 14 100 Microglia / field 12 12 80 # pTau / field neurons / field 10 10 % Intact 60 8 8 CA1 6 6 40 DG Source: Adapted from Ilievski, et al. 4 4 Chronic oral application of a 20 2 2 periodontal pathogen results in brain 0 0 0 inflammation, neurodegeneration and amyloid beta production in wild type mice PLOS: One 2018 *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 3x oral P.g. / week COR388 10 or 30 mg/kg po 2x/day 10 weeks 5 weeks 0.20 2.5 6,000 10,000 * 2.0 8,000 0.15 Copy # / 100 ng DNA Interneurons / mm 3 pg / mg Protein ** pg / mg Protein 4,000 1.5 6,000 0.10 1.0 4,000 *** 2,000 0.05 *** 0.5 2,000 0.0 0.00 0 0 Infected COR388 Infected COR388 Infected COR388 Infected COR388 Inf + Inf + Inf + Inf + Source: Dominy et al, 2019; Mean +/- SEM *p< 0.05,**p<0.01, ***p<0.001

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)

ApoE fragments are found in AD brain Full length ApoE Low MW ApoE fragments 10 Source: Huang et al 2001 (Gladstone), Mouchard et al 2019, Western blot: Cortexyme studies

ApoE is cleaved by P . gingivalis infected cells, ApoE4 > ApoE3 + ApoE3 + ApoE4 37kDa Full length ApoE 20kDa ApoE fragments 15kDa Source: Cortexyme studies 11

Putative Gingipain Cleavage Sites Lie Within Important Functional Domains Lipid Receptor Hinge Binding Binding Region Hinge Receptor Lipid Binding Binding 112 158 NH 2 ApoE2 Cys COOH Cys ApoE3 NH 2 Arg COOH Cys ApoE4 NH 2 Arg COOH Arg Receptor Binding aa140-150: LDLR binding aa139-152: C1q binding aa136** = Christchurch mutation, resulting in R to S change Source: Cortexyme studies

Gingipains fragment ApoE and preferentially ApoE4 # peptides detected by mass spec 700 600 Mass Spec detection of peptides produced from 500 gingipain (Kgp+RgpB) digestion of ApoE3 and ApoE4 400 Undigested (0 min) and digested (1 minute) 300 200 Each color represents unique peptides produced 100 0 E4 E3 E3 E4 1 min 0 min 1 min 0 min 13 Source: Cortexyme studies

Full length endogenous ApoE is reduced in infected astrocytes, effect is blocked by COR388, gingipain inhibition Infection + COR388/613 Infection + COR388 Infection + COR613 COR388/613 Infection Control Human iPSC-derived astrocytes (APOE3/4 genotype) APOE GAPDH Source: Cortexyme studies 14

ApoE fragmentation by gingipains will affect synapses and complement regulation ApoE is important for synaptic ApoE is important for regulation of C1q maintenence classical complement pathway adapted from Barres and Smith, Science 2001, adapted from Yin et al, Nature Med. Nov;(294)5545:1296-1297 2019 Mar;25(3):496-506

ApoE fragments are found in AD patient CSF and can be reduced by COR388 treatment CSF ApoE fragments are ApoE fragments reduced in Phase 1b found in AD CSF 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 Proportion Preposition: total content CANTAB composite (Z score) MMSE Score Days of treatment Days of treatment Days of treatment Placebo (n=3) COR388 (n=6) Source: Cortexyme Phase 1b study: *p< 0.05, ***p<0.001

Phase 2/3 GAIN Trial Mild-to-moderate AD US and EU Approximately 90 sites in US and EU 570 patients Image Subtitle Topline results Q4 2021 18

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 • 19