Article
NeuroVoices: Mike Detke, MD, PhD, on Atuzaginstat’s Potential in Alzheimer Disease, Periodontal Disease
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The chief medical officer of Cortexyme discussed the company’s investigational agent atuzaginstat, its mechanism of action, and the findings of the phase 2/3 GAIN trial.
Mike Detke, MD, PhD
The need for treatments for patients with Alzheimer disease (AD) remains a high priority, and a new, uniquely designed drug is making its way through the clinical pipeline. Cortexyme’s atuzaginstat, a novel bacterial virulence factor inhibitor previously known as COR388, has been shown to be well-tolerated in a phase 1 setting, with additional trends of efficacy on clinical scales and significant improvement on a computerized speech assessment and 2 relevant biomarkers. The phase 2/3 GAIN trial (NCT03823404), designed to be potentially pivotal for the therapy, completed enrollment in November 2020 and is expected to have topline efficacy data on the drug published in December 2021.
The novel mechanism of action of atuzaginstat is based on the discovery of gingipains, toxic protease virulence factors from the bacterial pathogen, porphyromonas gingivalis (Pg), which are found in more than 90% of brains with AD. At the 2021 Alzheimer’s Association International Conference, July 26-30, Mike Detke, MD, PhD, chief medical officer, Cortexyme, presented an update and baseline data from GAIN on behalf of the company. He noted that the enrolled subjects have characteristics consistent with AD and Pg infection, indicating an appropriate population to test the efficacy and safety of atuzaginstat.
On a new iteration of NeuroVoices, Detke discussed the GAIN trial in its entirety, including why its dental substudy sets it apart from traditional AD clinical trials. He also provided in-depth detail on unique mechanism of atuzaginstat, what has been previously observed with Pg in AD, and the associations between periodontal disease and AD.
NeurologyLive: Can you provide an overview on the phase 2/3 GAIN study?
Mike Detke, MD, PhD: The phase 3 GAIN trial is designed to be a gold standard test of this drug for disease modification in patients with mild to moderate Alzheimer disease, corresponding to Mini Mental State Exam scores between 24 and 12, inclusive at the outset of the study. We’ll be treating patients for a year, using widely accepted co-primary outcomes of the ADAS-Cog, which measures cognition, and the ADCS-ADL, which measures activities of daily living or ability to function. We’re looking at a lot of biomarkers and traditional secondary outcomes as well, including traditional biomarkers such as amyloid, tau, etc.
The GAIN trial has 2 features that are quite unique. First, we’re looking at a number of different biomarkers related to infection with porphyromonas gingivalis, our purported causal agent. We’ll look at biomarkers of porphyromonas gingivalis, biomarkers of inflammation, and so forth. The other aspect that is unique is that about 40% of the patients went to clinical trial sites that had a nearby affiliated dental site. They’re getting dental exams done too which is important for several reasons. We think, and it’s been reported in the literature too, that this is the key bacterium or causal agent in periodontal disease or advanced gum disease. We want to see if the drug is effective there as well. It’s statistically powered to have a 90% chance to see 50% reduction in decline, the decline typically seen in Alzheimer disease.
Why is atuzaginstat’s mechanism so effective to treat this population?
It has a unique and interesting mechanism. The theory is that this bacterium, porphyromonas gingivalis, colonizes the mouth and gets into the brain. The bacterium is unusual in 2 ways. One is that it gets inside of the cells. It’s an intracellular bacterium, which is very unusual. The other is that its asacralytic, meaning it doesn’t live off sugars for its food, or fuel, it lives off proteins. Those 2 features together make it damaging because it gets inside of cells to feed on proteins. It releases proteases, or molecules that chop up other proteins. Those proteases go around inside the body, chopping up tau and APOE, and basically the cell infrastructure. In a medical way, it’s essentially digesting the cell from within. It’s a little like having termites in your brain cells or in your gum tissue.
It has also developed some immune evasion strategies that make it hard to get rid of. Because its intracellular, some antibiotics don’t get to it. In the mouth, it often lives in these plaques, which antibiotics don’t penetrate. It can become dormant and antibiotic resistant. We’ve known over the years that you can’t treat periodontal disease or Alzheimer disease with a week’s worth of antibiotic. We know we can’t kill the bacterium. What we did is develop a drug that targets those proteases, which are causing all the damage inside the cell.
Our drug binds covalently, thereby irreversibly inactivating those proteases. That has 2 effects. First, since these gingipain proteases are causing all the damage in the pathology, once you get rid of them you take that all away. You also starve off the food supply of protein fragments to the bacterium. You see the level of bacterium going down significantly. It’s hard to get rid of the bacterium completely because it goes dormant and its endemic in the population. Our hypothesis is that this will probably need a long-term treatment.
As for its efficacy, I’m excited because there’s so much converging evidence that supports this theory and support that it will be efficacious. Multiple papers published by third party sources have showed that the biggest 2 risk factors for Alzheimer disease are lower level of education and periodontal disease. That’s 1 piece of evidence. We’ve showed in a mouse model that if you take rub porphyromonas gingivalis on regular non-genetically modified mice, they all get the pathology of Alzheimer disease plaques, tangles, inflammatory markers like TNF alpha. That mouse model has been replicated by 5 independent labs. Replication and verification by fellow sciences is an important part of the process.
Working with a third-party group, the University of Aukland, we looked at a brain bank of patients with Alzheimer and age-matched controls and saw that gingipains occurred in almost 95% of cases. Our phase 1 data is encouraging. Our baseline data from the phase 2/3 GAIN trial support the hypothesis. GAIN is an Alzheimer disease trial. We’re looking at periodontal disease, but the primary goal is in mild to moderate Alzheimer disease. We recruited patients with Alzheimer disease, but had no entry criteria required for periodontal disease or even encouraging people with periodontal disease. Among the population that got dental exams at baseline, a little over 90% of them had moderate to severe periodontal disease. The background rate in the population at this age is more like 40% to 50%. The fact that we have 90% of a cohort of 200 is certainly highly statistically significant and supports the idea that there’s a single cause behind both Alzheimer disease and periodontal disease. All this converging evidence is what makes me enthusiastic about seeing the results of the GAIN trial next quarter.
Transcript was edited for clarity.
