SAN DIEGO & SOUTH SAN FRANCISCO, Calif.--(BUSINESS WIRE)--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.”
“Recent research has shown that the APOE gene may play a larger role than previously believed in Alzheimer’s disease development, suggesting that a solid understanding of APOE is important to a comprehensive hypothesis of Alzheimer’s causation,” said Casey Lynch, Cortexyme’s chief executive officer, co-founder, and chair, and a co-author of today’s presentation. “We believe the data presented today provide insight into why APOE4 increases the risk for Alzheimer’s disease: the ApoE4 protein, which is important for synaptic maintenance and control of neuroinflammation, has a higher propensity to be fragmented by gingipains, compared to other forms of ApoE. Importantly, our human studies have shown the ability of COR388 to protect ApoE proteins from gingipain fragmentation in the brains of study subjects.”
A growing body of evidence points to P. gingivalis as playing a key role in the development of Alzheimer’s disease given its identification in the brains of AD patients and its ability to cause neurodegeneration, inflammation, beta-amyloid and tau buildup, and other pathology associated with the disease in animal models. An asacchrolytic bacterium, P. gingivalis has been shown to infiltrate the brain and release toxic proteases called gingipains that cleave ApoE, tau, and other proteins associated with neuronal function. Cortexyme is developing COR388, an investigational small-molecule gingipain inhibitor that is currently in a large, international Phase 2/3 clinical trial (the GAIN Trial). This trial is evaluating the efficacy, safety, and tolerability of COR388 in patients with mild to moderate AD, with top-line results expected in the fourth quarter of 2021.
About Cortexyme, Inc.
Cortexyme (Nasdaq: CRTX) is a clinical stage biopharmaceutical company pioneering a novel, disease-modifying therapeutic approach to treat what it believes to be a key underlying cause of Alzheimer’s disease and other degenerative diseases. Cortexyme is targeting a specific, infectious pathogen found in the brain of Alzheimer’s patients and tied to neurodegeneration and neuroinflammation in animal models. The company’s lead investigational medicine, COR388, is the subject of the GAIN Trial, an ongoing Phase 2/3 clinical study in patients with mild to moderate Alzheimer’s. To learn more about Cortexyme, visit www.cortexyme.com or follow @Cortexyme on Twitter.
Statements in this press release contain “forward-looking statements” that are subject to substantial risks and uncertainties. Forward-looking statements contained in this press release may be identified by the use of words such as “anticipate,” “expect,” “believe,” “will,” “may,” “should,” “estimate,” “project,” “outlook,” “forecast” or other similar words. Forward-looking statements are based on Cortexyme’s current expectations and are subject to inherent uncertainties, risks and assumptions that are difficult to predict. Further, certain forward-looking statements are based on assumptions as to future events that may not prove to be accurate. Factors that could cause actual results to differ include, but are not limited to, the risks and uncertainties described in the section titled “Risk Factors” in the final prospectus related to Cortexyme’s initial public offering filed with the Securities and Exchange Commission on May 9, 2019 and Quarterly Report on Form 10-Q filed with the Securities and Exchange Commission on November 12, 2019. Forward-looking statements contained in this press release are made as of this date, and Cortexyme undertakes no duty to update such information except as required under applicable law.