Gum disease bacteria, a new therapeutic target for Alzheimer’s disease?

New research suggests that an experimental oral drug that targets bacteria that cause gum disease may offer a “new treatment paradigm” for mild to moderate Alzheimer’s disease (AD).

Dr Michael Detke

Results of the Phase 2/3 GAIN trial of atuzaginstat (Cortexyme Inc), which targets gum bacteria Porphyromonas gingivalis (Pg), suggest that the pathogen is a “potential driver of Alzheimer’s disease”.

“We have shown the efficacy and safety of our drug in patients with mild to moderate AD who have Pg infection; and we believe we have found an optimal dose. This represents a whole new treatment paradigm for AD, ”study investigator Michael J. Detke, MD, PhD, chief medical officer at Cortexyme, said Medscape Medical News.

The results were presented at the 14th Alzheimer’s Disease Clinical Trials Conference (CTAD).

Chronic low-grade infection

Pg is associated with gum disease, including gingivitis and periodontal disease. Detke added that periodontal disease affects approximately 65 million Americans.

Previous research has linked periodontal disease to an increased risk of AD. A study cited by Detke showed that individuals with severe gum disease decreased by six points on the AD-Cognitive Subscale (ADAS-Cog) rating scale in 6 months compared to just one. point among those with mild or no periodontal disease.

The evidence linking inflammation to AD is “consistent with the idea that there is … a chronic low-grade infection that causes this inflammatory response,” Detke said.

He noted that 22 of the last 25 genetic risk factors identified for AD are related to the function of the immune system.

Pg is different from other bacteria in that it gets inside cells and depends on protein for energy instead of sugars or carbohydrates. The bacteria release proteases called gingipains that “cut” proteins into fragments that provide energy, Detke said.

Atuzaginstat is designed to stop damage caused by gingipain protease by cutting off the bacteria’s food supply. Because Pg is inside cells and “can go dormant or develop resistance,” it’s extremely difficult to remove it completely with typical antibiotics, Detke noted.

Slow cognitive decline

The GAIN trial included 643 generally healthy patients aged 55 to 80 years (mean age, 69 years) with mild to moderate AD, as measured by a score of 12 to 24 on the mini-exam. mental state. About 65% were ApoE4 carriers.

All participants were randomized to receive placebo or a low dose (40 mg twice daily) or high dose (80 mg twice daily) atuzaginstat for 48 weeks.

In addition to standard cognitive results, the researchers assessed Pg biomarkers in saliva, blood, and cerebrospinal fluid (CSF).

The two primary outcomes were scores from the ADAS-Cog and AD Cooperative Study-Activities of Daily Living (ADCS-ADL) study. The results showed that none of these results were significant in the entire intention-to-treat cohort.

However, when investigators looked only at participants with more severe Pg infection, there was a correlation between lower Pg levels and better clinical outcomes.

“In people with high levels of Pg in saliva, serum, and CSF – in all of these cases – you saw a significant slowdown in the decline on ADAS-Cog – from 26% to 57%,” Detke said.

Another statistical analysis showed a slowing of cognitive decline from 40% to 56%.

“According to the AD literature, 20 or 30% is good, so seeing 40 or 50% is really more than anything anyone has seen, especially in this difficult to moderate population,” he added.

A causal pathogen?

There were also correlations between Pg levels in saliva at 24 weeks and clinical outcomes at 24 and 48 weeks. “If Pg is causal then a 24 week change could predict clinical impact at both time points and that’s what we saw,” the results being “quite highly significant,” Detke said.

“There are hardly any other studies in AD that have shown a correlation between a biomarker and clinical outcomes,” he noted.

Looking at bilateral hippocampal volume, the researchers also found that the drug slowed down atrophy – by 22% in the lower dose group and by 11% in the higher dose group. Efficacy was comparable for the 40 mg and 80 mg doses.

There was little difference between men and women, APOE carriers and non-carriers, or between patients with mild or moderate disease. “It appears to work for anyone with a high level of infection,” Detke said.

The most common side effects were gastrointestinal (GI), including nausea and diarrhea. This makes sense because Pg is found in the gastrointestinal tract and likely affects the microbiome to some extent, Detke noted.

Overall, the rates of serious adverse events (SAEs) were too low to draw any conclusions, he said. However, SAEs were reported in 19 members of the placebo group, 20 in the low dose group and 25 in the high dose group.

There were two cases of bilirubin elevation, both in the high dose group. There were also five deaths in the high dose group, but they were not found to be drug related.

There was no concern with amyloid-related imaging abnormalities (ARIA), “which is a big advantage over amyloid drugs,” Detke said.

The drug does not completely eliminate the bacteria, he noted. Given to animals infected with Pg, it “reduces the levels of the bacteria by 80 to 90%, but does not eliminate it,” he added. “So it’s probably a chronic treatment for the rest of life” similar to a protease inhibitor used to treat HIV, Detke said.

More research needed

Commenting on the search for Medscape Medical News, Rebecca Edelmayer, PhD, senior director of scientific engagement at the Alzheimer’s Association, said it was “encouraging” to see approaches that look at the disease from new angles.

“We learn something new from every try,” Edelmayer said.

“Research on this particular approach is expected to continue and we look forward to seeing the performance of this drug in future clinical trials,” she added.

The study was funded by Cortexyme Inc. Detke is a full-time employee of Cortexyme and holds shares in the form of stock options. Edelmayer did not disclose any relevant financial relationship.

14th Alzheimer’s Disease Clinical Trials Conference (CTAD): Last Minute Reading Roundtable # 6. Presented on November 11, 2021.

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