GAIN Study Tests Gum Disease-Associated Protein as Target for Disease-Modifying Treatment of Alzheimer Disease
Characteristics of the study design and population for the ongoing phase 2/3 GAIN trial (NCT03823404) of atuzaginstat (COR338; Cortexyme, South San Francisco, CA) were presented at the Alzheimer Association International Conference July 26-30, 2021. Atuzaginstat is an inhibitor of gingipain—a protein from the bacteria P. gingivalis, known primarily for its causative role in gum disease that may also play a causative role in Alzheimer disease (AD).
This trial is novel in targeting a possible disease mechanism "upstream of," or occurring before the well-known amyloid β (Aβ) plaque, tau tangles, neuroinflammation, and neurodegeneration of AD. The GAIN trial also differs from many other ongoing trials in that participants have mild-to-moderate AD dementia, defined as Mini-Mental State Examination (MMSE) scores of 12 to 24.
Although AD biomarkers were not among the inclusion criteria, baseline data of enrolled participants show they are relatively homogeneous for AD biomarkers, including cerebrospinal fluid (CSF) levels of Aβ1-42:Aβ1-40 ratio, total tau, and phosphorylated tau (phospho-tau). By these measures, over 84% of participants have biomarker-positive AD. All participants also have evidence of P. gingivalis exposure. Of note, participants also have higher levels of the inflammatory biomarker α-2-macroglobulin (A2M) and von Willebrand factor, which is a marker of vascular endothelial damage.
Dr. Marwan Sabbagh, MD, director of Translational Health and Camille and Larry Ruvo Endowed Chair for Brain Health, Cleveland Clinic Lou Ruvo Center for Brain Health, Las Vegas, NV and principal investigator on the GAIN study said, "preclinical and phase 1 data support potential efficacy of COR338 to treat AD. Testing this with 2 different doses vs placebo in a population that is well-defined, meeting both clinical and biomarker criteria for mild-to-moderate AD, gives us confidence that observed results will be easy to evaluate for this specific population with high unmet need." Dr. Sabbagh notes that he receives consultancy fees from Cortexyme but holds no financial interest in the company.
Mike Detke, MD, PhD, chief medical officer of Cortexyme said, "among the most exciting aspects of this trial is that as the study population is defined, if efficacy is proven, we could have treatment for mild-to-moderate AD without the need for amyloid or tau imaging. An effective treatment for mild-to-moderate AD alone would address considerable unmet need for this devastating disease. Considering the possible upstream mechanism, we certainly hope it could eventually be tested for earlier stages of AD or even preventive treatment as we cover the mildest AD already.”
There are associations between gum disease, tooth loss, and AD in humans, including longitudinal studies suggesting gum disease may precede AD development. In a phase 1 clinical trial, 6 individuals with AD treated with atuzaginstat had statistically significant improvements in AD-associated biomarkers and performance on a computerized language test compared with 3 participants with AD treated with placebo. Improvements in MMSE scores occurred, although these did not reach statistical significance. No safety concerns arose during this phase 1 trial.
In mice, when P. gingivalis is applied to teeth and gums, it infects the brain, resulting in AD-pathology, including Aβ plaques, phospho-tau, neuroinflammation, and hippocampal neuron loss. Treating these mice with atuzaginstat causes statistically significant reductions in brain levels of P. gingivalis, DNA, Aβ, phospho-tau, and tumor necrosis factor α (a marker of neuroinflammation) and increases the number of hippocampal interneurons.