Most of the mild to moderate Alzheimer’s patients enrolled in the atuzaginstat (COR388) Phase 2/3 trial show evidence of systemic infection due to Porphyromonas gingivalis, a bacteria linked to periodontal disease whose toxic enzymes are thought to contribute to Alzheimer’s and are targets for this candidate therapy.
A “high proportion” also test positive for biomarkers associated with this neurodegenerative disease.
“The baseline biomarker and P. gingivalis characteristics reported today give us confidence that we have enrolled an appropriate patient population for testing the efficacy of atuzaginstat in the GAIN Trial,” said Michael Detke, MD, PhD, chief medical officer for Cortexyme.
Data was presented during the oral session “Phase 2/3 GAIN trial of COR388 (atuzaginstat), a novel bacterial virulence factor inhibitor for the treatment of Alzheimer’s disease: Update and baseline Data,” at the 13th Clinical Trials on Alzheimer’s Disease Conference (CTAD), held online Nov. 4–7.
Atuzaginstat is a small molecule inhibitor of gingipains, the enzymes produced and released by P. gingivalis that have been found in more than 90% of post-mortem patient brain samples. These toxic enzymes are also known to trigger Alzheimer’s in animal models.
By block these enzymes, which are also thought to contribute to disease progression, atuzaginstat may be able to slow, or stop, the continuous neurodegeneration observed in patients.
GAIN, a Phase 2/3 trial, is assessing the safety, tolerability, and efficacy of two doses of oral atuzaginstat — 80 or 40 mg capsules taken twice daily — compared with a matched placebo, in adults with mild to moderate Alzheimer’s.
Fully enrolled with 643 patients randomly assigned to treatment or placebo, its main goals are changes in cognition, dementia severity, and overall participation in daily life activities (function) from the study’s start (baseline) through 48 weeks (about one year).
Changes in patients’ cognition will be assessed using the Alzheimer’s Disease Assessment Scale-Cognitive Subscale 11 (ADAS-Cog 11), dementia via the Clinical Dementia Rating-Sum of Boxes (CDR-SB), and function by the Alzheimer’s Disease Cooperative Study Group-Activities of Daily Living (ADCS-ADL).
Secondary and exploratory study goals include assessing changes in several cerebrospinal fluid (CSF) disease biomarkers, MRI parameters, and other measures. (CSF is the liquid that circulates in the brain and spinal cord.)
GAIN also includes a sub-study looking at the effects of atuzaginstat on symptoms of gum disease, including the depth of gingival pockets. Interim trial data is expected in December, and top-line data in late 2021.
At the conference, the company presented data from an analysis of baseline patient characteristics covering 40–50% of all those enrolled (data available as of Oct. 15), and showing a majority had an adequate profile for responding to atuzaginstat.
Specifically, 75% had an amyloid beta (Aβ) 42/40 — a biomarker of Alzheimer’s — ratio associated with the disease, and around 88% had a low Aβ 42/40 ratio associated with the presence of amyloid plaques in a positron emission tomography (PET) scan.
Most of these patients also had high levels of tau (89%) and phosphorylated tau protein (86%), two other CSF biomarkers of Alzheimer’s.
All patients tested to date showed signs of systemic infection caused by P. gingivalis, with 72% having high levels of circulating antibodies associated with severe gum disease, and 97% had antibody levels associated with at least mild gum disease. Of note, antibody levels are known to roughly correlate with infection and bacteria load.
Data from GAIN’s gum disease sub-study also showed that more than 90% of patients evaluated had moderate to severe gum disease at the time of enrollment.
“Cortexyme remains on track to conduct an interim analysis of the GAIN Trial in December 2020,” Detke said.
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