Porphyromonas gingivalis (Pg) plays a role in driving Alzheimer’s disease (AD) pathology, according to researchers at Cortexyme. But the privately held, clinical-stage pharmaceutical company also is developing small-molecule inhibitors that block the pathogen and could halt the development and progression of the disease.
“Infectious agents have been implicated in the development and progression of Alzheimer’s disease before, but the evidence of causation hasn’t been convincing,” said Stephen Dominy, MD, cofounder and chief scientific officer of Cortexyme and lead author of the study.
“Now, for the first time, we have solid evidence connecting the intracellular, Gram-negative pathogen, Pg, and Alzheimer’s pathogenesis while also demonstrating the potential for a class of small-molecule therapies to change the trajectory of the disease,” Dominy said.
In mouse models, oral Pg infection led to brain colonization and increased production of amyloid beta (Aβ), a component of the amyloid plaques commonly associated with AD. The researchers also detected Pg’s toxic proteases, or gingipains, in the neurons of AD patients.
The researchers correlated the gingipain levels with pathology related to two markers: tau, a protein needed for normal neuron function, and ubiquitin, a small protein tag that marks damaged proteins for degradation and is found in tau angles and Aβ plaques. The gingipains were found to be neurotoxic in vivo and in vitro, exerting detrimental effects on tau.
Seeking to block Pg-driven neurotoxicity, the researchers designed a series of small-molecule therapies targeting Pg gingipain. They demonstrated that inhibition by COR388 reduced the bacterial load of an established Pg brain infection, blocked Aβ42 production, reduced inflammation, and protected neurons in the hippocampus, a part of the brain that mediates memory and frequently atrophies early in AD development.
In October 2018, Cortexyme announced the results of its Phase 1b clinical trial of COR388 and called it safe and well tolerated in healthy older volunteers and AD patients when given at a range of doses for up to 28 days.
COR388 was detectable in the cerebral spinal fluid along with fragmented DNA from the bacterium that it targets. COR388 also showed positive trends across several cognitive tests in AD patients. Cortexyme plans to initiate a large Phase 2/3 clinical trial in patients with mild to moderate AD this year.