Trial Data Further Support Gingipain Suppression as Potential Therapy
Atuzaginstat (COR388), Cortexyme’s investigational oral therapy, effectively suppressed the activity of its target — toxic enzymes called gingipains — and was associated with reductions in several disease biomarkers in people with mild-to-moderate Alzheimer’s, according to updated data from the Phase 2/3 GAIN clinical trial.
Similar to previously reported findings, these benefits were most pronounced among patients with high load of Porphyromonas gingivalis (P. gingivalis), a bacterium that produces gingipains, causes gum disease, and has been linked to Alzheimer’s development.
Greater reductions in P. gingivalis biomarkers also were associated with better outcomes.
These additional results from the GAIN study (NCT03823404), completed in January, were shared recently in an oral presentation at the 2022 International Conference on Alzheimer’s and Parkinson’s Diseases, held March 15–20 in Barcelona, Spain, and virtually.
The presentation was titled “Additional Data from the Phase 2/3 GAIN Trial of COR388 (Atuzaginstat) for the Treatment of Mild to Moderate Alzheimer’s Disease.” It is the first of several presentations anticipated by Cortexyme to share additional GAIN trial data throughout the year.
“Our understanding of the impact of lysine gingipain inhibition [suppression] on neurodegeneration and other Alzheimer’s disease markers continues to expand,” Michael Detke, MD, PhD, Cortexyme’s chief medical officer, said in a press release.
“The evidence demonstrates our target – P. gingivalis – may play a key upstream role in both of these areas, and correlations between P. gingivalis biomarkers and clinical assessments show that our ability to inhibit this target potentially leads to improved patient outcomes,” Detke added.
These findings “provide critical insights to help us advance our gingipain inhibitor pipeline, expanding upon and supporting clinical evidence of this target and atuzaginstat’s mechanism of action, in addition to helping us better identify which patients are most likely to benefit,” Detke said.
Earlier this year, the U.S. Food and Drug Administration placed a full hold on atuzaginstat’s clinical development, likely due to liver-related safety concerns detected by the agency last year.
Cortexyme now will prioritize the development of COR588, a next-generation gingipain suppressor that, according to the company, showed more favorable safety and pharmacological profiles in preclinical studies. The therapy is being tested in healthy volunteers in a Phase 1 trial, with results expected this year.
An increasing body of evidence points to P. gingivalis infection as a driver of Alzheimer’s disease. Gingipains, the enzymes produced by P. gingivalis to help them grow and survive, have been found in 90% of brains of Alzheimer’s patients, and associated with disease biomarkers and symptoms.
Also, spouses of Alzheimer’s patients have a six times greater risk of developing the disease, which is consistent with an infectious cause, and oral P. gingivalis infection in mice recreates Alzheimer’s features, which can be reversed with atuzaginstat treatment.
As such, atuzaginstat is expected to help slow or prevent further neurodegeneration in people with Alzheimer’s.
To confirm this hypothesis, Cortexyme launched the Phase 2/3 GAIN trial, which evaluated the safety and effectiveness of atuzaginstat in 643 adults, ages 55 to 80, with mild-to-moderate Alzheimer’s.
Participants, recruited at more than 90 sites across the U.S. and Europe, were assigned randomly to receive an oral capsule of either 40 or 80 mg of atuzaginstat, or a placebo, twice daily for 48 weeks (nearly a year).
Previous top-line results showed that atuzaginstat was generally safe, but was not superior to a placebo at slowing cognitive or daily functioning decline, failing to meet its main goals for the whole patient population.
However, prespecified analysis among patients with high P. gingivalis load showed significant treatment responses among those in whom the bacterium’s DNA was detected in their saliva, or high levels of anti-P. gingivalis antibodies were detected in the blood.
Specifically, atuzaginstat was associated with a 30–50% slower cognitive decline in these patient subgroups. Also, greater P. gingivalis DNA reductions in patients’ saliva were associated significantly with improved cognitive and mood outcomes.
The therapy also was generally safe, with most adverse effects being mild-to-moderate in severity.
However, increases in liver enzymes — suggestive of liver damage — were 10 times more likely among patients given atuzaginstat’s high dose than among those on a placebo. Two of these reactions were deemed serious and likely related to the therapy.
Newly presented data showed that atuzaginstat significantly reduced the activity of gingipain K, one of the main gingipain enzymes produced by P. gingivalis, in gum samples of a subset of patients with gum disease at about six months and one year. This confirmed the therapy’s target engagement.
In addition, the therapy was associated with a trend of reduction in the levels of toxic molecules involved in Alzheimer’s, including beta-amyloid and tau protein.
These beneficial trends also were present in the prespecified group of patients with P. gingivalis detected in the saliva, “which are the most likely responders, consistent with the gingipain hypothesis and atuzaginstat’s efficacy,” Cortexyme stated in the press release.
Trends of lower rates of decline were detected in three measures of brain volume, particularly in the prespecified group of the most likely responders. Notably, lower brain volume decline was associated significantly with slower cognitive and functional decline.
Overall, these findings further support a role of P. gingivalis in Alzheimer’s progression.
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