COR388 (atuzaginstat): an investigational gingipain inhibitor for the treatment of Alzheimer disease

ABSTRACT

Introduction

Evidence from in vitro and in vivo studies demonstrates that amyloid beta (Aβ) oligomers have potent, broad-spectrum antimicrobial properties created by fibrils that entrap pathogens and disrupt their membranes. Data suggest that Aβ may play a protective role in the innate immune response to microbial infections and that Aβ in the brain plays a damaging role when the inflammatory response is not well controlled.

Areas covered

This paper describes the relationship between periodontal disease and Alzheimer disease (AD), the role of Porphyromonas gingivalis and its secreted gingipains in AD, and the potential of the gingipain inhibitor atuzaginstat (COR388) to modulate AD neuropathologies.

Expert opinion

P. gingivalis is opsonized by Aβ42, is capable of entering the brain, and is an accelerant of neuropathologies in rodent models of AD. Thus, in our opinion, this bacteria is highly likely to be a pathogen capable of initiating or precipitating the progression of AD, which agrees with the pathogen hypothesis of clinical AD development.

KEYWORDS:

• Alzheimer disease
• atuzaginstat
• clinical trials
• gingipain
• neuroinflammation
• periodontal disease
• Porphyromonas gingivalis

Article highlights

• Amyloid beta (Aβ) might have natural antimicrobial properties.

• The link between periodontal disease and Alzheimer disease (AD) might not be incidental and is likely to be mechanistic.

• Porphyromonas gingivalis and its proteases, called gingipains, are neurotoxic and trigger neuroinflammatory pathways.

• Atuzaginstat is the first-in-class gingipain protease inhibitor and has been shown to reduce AD pathology and inflammatory markers.

• Clinical trials of atuzaginstat have demonstrated efficacy in a subset of patients who express P. gingivalis DNA, but drug development has been hampered by emerging hepatotoxicity.

Acknowledgments

The authors thank the staff of Neuroscience Publications at Barrow Neurological Institute for assistance with manuscript preparation.

Declaration of interest

M Sabbagh discloses ownership interest (stock or stock options) in NeuroTau, Inc., Optimal Cognitive Health Company, uMETHOD, Athira Pharma, Inc., and Cognoptix, Inc.; consulting for Alzheon, Inc., Biogen Idec, GmbH, Cortexyme, Inc., Genentech (Roche Group), Acadia Pharmaceuticals, Inc., T3D Therapeutics, Inc., Eisai Co., Ltd., Eli Lilly and Co., and KeifeRx. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

A reviewer on this manuscript has disclosed serving as a member of the clinical advisory board of Cortexyme Inc. – the company that developed the gingipain inhibitor, COR388/atuzuginstat – and receiving compensation as a consultant for this company. Peer reviewers on this manuscript have no other relevant financial relationships or otherwise to disclose.

Additional information

Funding

This paper was supported by grants from the National Institutes of Health (NIH): NIH R01AG059008, NIH P20AG068053, NIH P30AG072980, and NIH R01AG073212.