Cortexyme Announces Presentation of Data Revealing Link Between Bacterial Pathogen and Genetic Risk for Alzheimer’s Disease
Cortexyme, Inc. (Nasdaq: CRTX) today announced the presentation of new data supporting the on-target activity of COR388, its lead investigational medicine, and linking the “gingipain hypothesis” for Alzheimer’s disease (AD) to the significance of the APOE gene as a major risk factor for the disease. Michael Detke, M.D., Ph.D., the company’s chief medical officer, detailed the results in an oral presentation (abstract #OC28) at the 2019 Clinical Trials in Alzheimer’s Disease (CTAD) meeting, which is being held December 4-7, 2019 in San Diego.
Today’s CTAD presentation is centered on two findings related to the growing interest in ApoE fragmentation as a potential pathogenic mechanism for sporadic Alzheimer’s disease:
- Gingipains from P. gingivalis cleave ApoE proteins and have a preference for cleaving ApoE4; and COR388, a gingipain inhibitor, prevents this. In in vitro experiments, cells infected with P. gingivalis exhibited gingipain-dependent ApoE cleavage activity that generated ApoE fragments similar to what was seen in the brains and cerebrospinal fluid (CSF) of patients with Alzheimer’s disease. In contrast, uninfected cells had no significant ApoE protein-cleaving activity. Furthermore, P. gingivalis gingipains cleaved ApoE4 more readily than ApoE3. Finally, in the infected cells, COR388 alone was sufficient to block ApoE fragmentation.
- In a Phase 1b trial, COR388 reduced ApoE fragments in CSF. Cortexyme’s Phase 1 clinical development program for COR388 included cohorts of healthy volunteers and subjects with Alzheimer’s disease. In addition to assessing safety and initial clinical activity, investigators also assessed the level of ApoE fragmentation in the CSF of nine subjects with Alzheimer’s disease. Six subjects received 50mg of COR388 twice daily while three subjects received placebo. After 28 days, a statistically significant decrease in ApoE fragments (both ApoE4 and ApoE3) was observed in subjects treated with COR388 versus those treated with placebo.
“The APOE gene is known to significantly impact Alzheimer’s risk, with the APOE2 variant playing a protective role and APOE4 associated with a much higher risk for developing the disease,” said Dr. Detke. “The data presented today further illuminate the potential relationship between APOE-driven genetic risk and the presence of gingipains from P. gingivalis in the brain, which we have found in 90-100% of Alzheimer’s patients, depending on the method of measurement.”