All Patients in GAIN Trial Show Signs of Gum Disease Bacteria
Every participant in the Phase 2/3 GAIN clinical trial, which is testing Cortexyme’s experimental medication COR388 (atuzaginstat) in people with Alzheimer’s disease, showed evidence of infection by Porphyromonas gingivalis (P. gingivalis), according to a new analysis.
In particular, all patients analyzed at the beginning of the study who had available data on their cerebrospinal fluid — the liquid that surrounds the brain and spinal cord — were positive for antibodies against P. gingivalis, supporting a direct P. gingivalis infection in the central nervous system.
The findings add to a growing body of data supporting a link between P. gingivalis — a type of bacteria best known for causing gum (periodontal) disease — and Alzheimer’s.
The data were shared at the Annual Biomarkers for Alzheimer’s Disease Summit by Leslie Holsinger, PhD, executive vice president of research and development at Cortexyme. Holsinger’s presentation was titled “Use of Novel Biomarkers of P. Gingivalis Infection & Neuroinflammation in the GAIN Trial: An Ongoing Phase 2/3 Clinical Trial Assessing the Activity of Atuzaginstat in Patients with Mild to Moderate Alzheimer’s Disease.”
Holsinger opened with an overview of the evidence linking P. gingivalis with Alzheimer’s. For example, over 90% of Alzheimer’s patients show evidence of the bacteria in their brains upon autopsy, and people with Alzheimer’s who have active periodontal disease tend to have more severe disease. Additionally, some proteins, like amyloid-beta, that are characteristically dysregulated in Alzheimer’s are thought to have anti-microbial properties, and P. gingivalis has been shown to be capable of infecting brain cells.
COR388 is an oral small molecule that works to block the activity of gingipains, which are toxic enzymes released by P. gingivalis that have been linked with Alzheimer’s development.
In mouse models of P. gingivalis infection, treatment with COR388 reduced Alzheimer’s-like changes in the mice’s brain. The investigational therapy also showed potency against the bacteria in a naturally occurring dog model of gum disease.
Early clinical testing showed COR388 to be safe and well-tolerated in healthy volunteers, and results from a Phase 1b clinical trial (NCT03418688) that enrolled nine Alzheimer’s patients were positive: the six participants given COR388 showed a trend toward better cognition than the three given a placebo.
The GAIN trial (NCT03823404) has enrolled 643 participants, ages 55 to 80, with mild to moderate Alzheimer’s. Participants in the ongoing trial are being given 40 or 80 mg of COR388, or a placebo, twice daily. The study’s main goal is to evaluate the effect of treatment on standard measures of cognition and function after 48 weeks (about a year).
In her presentation, Holsinger shared available biomarker data from the trial. (Biomarkers are molecules that can be measured in blood or other bodily fluids to give information about health or disease.)
Analyses of the cerebrospinal fluid (CSF) of trial participants showed that 84% had high levels of well-established Alzheimer’s biomarkers, such as amyloid-beta and tau.
Furthermore, out of 638 participants with available data, all tested positive for antibodies against P. gingivalis in their blood. Antibodies are proteins made by the immune system to fight infections, and a given antibody will only recognize a single type of molecular target, called an antigen. As such, the presence of antibodies against P. gingivalis suggests that these patients had been infected with the bacteria at some point.
Over three-quarters (78%) of the participants had unusually high levels of these antibodies, of the sort that would often accompany symptoms of gum disease.
Moreover, of the 472 participants with available CSF samples, all of them had anti-P. gingivalis antibodies in their CSF. Conceptually, antibodies in the CSF could come from two places: from inside the nervous system, or from elsewhere in the body.
To investigate the source of these antibodies, researchers assessed the CSF/serum albumin index, a marker of the functionality of the blood-brain barrier (BBB). The BBB regulates what substances in the blood can get into the brain. Nearly all (98%) of participants in GAIN showed signs of a functional BBB.
Statistical analyses revealed no correlation between BBB dysfunction and the Alzheimer’s-associated proteins amyloid-beta and tau, supporting the idea that these proteins originate in the brain.
There also was no correlation between BBB dysfunction and anti-P. gingivalis antibodies in the CSF, suggesting that these antibodies may originate from within the nervous system itself.
“The presence of these antibodies further supports a direct P. gingivalis infection in the central nervous system [the brain and spinal cord],” the researchers concluded.