Experimental drug COR388 shows promise
- Cortexyme researchers reported on January 23, 2019 that experimental drug COR388 lowered Porphyromonas gingivalis burden and amyloid-beta in preclinical Alzheimer’s models. (science.org) - Science Advances said oral P. gingivalis infection in mice increased Aβ1-42, while small-molecule inhibitors including COR388 reduced bacterial DNA in brain tissue. (science.org) - ClinicalTrials.gov lists the Phase 2/3 GAIN study of COR388 in Alzheimer’s disease, while larger human evidence remained unresolved after later safety setbacks. (clinicaltrials.gov)
Stephen Dominy and Casey Lynch reported in a January 23, 2019 Science Advances paper that Porphyromonas gingivalis, a bacterium linked to chronic gum disease, was found in the brains of Alzheimer’s patients and that small-molecule gingipain inhibitors including COR388 showed activity in animal models. (science.org) The paper said oral infection with P. gingivalis in mice led to brain colonization and higher production of Aβ1-42, a component of amyloid plaques. The authors wrote that treatment with the inhibitors reduced bacterial load and downstream markers tied to neurodegeneration in those models. ### What exactly did COR388 do in the lab? The 2019 paper said COR388 was designed to inhibit gingipains, toxic proteases secreted by P. gingivalis. (clinicaltrials.gov) In the mouse experiments described in the paper, gingipain inhibition reduced the abundance of P. gingivalis DNA in brain tissue and mitigated neurotoxic effects associated with infection. Mark Ryder, writing in the Journal of Periodontology in 2020, summarized the same line of research by saying oral administration of gingipain inhibitors to mice with established brain infections decreased P. gingivalis DNA in the brain and lessened neurotoxic effects. Ryder also wrote that gingipains had been found in association with neurons, tau tangles and beta-amyloid in brain samples from people with Alzheimer’s disease. (science.org) ### Why are gum bacteria part of an Alzheimer’s story? Porphyromonas gingivalis is a pathogen commonly associated with periodontitis, according to the Journal of Periodontology review and the Alzheimer’s Drug Discovery Foundation report on gingipain inhibitors. (science.org) The hypothesis tested by Cortexyme and collaborators was that brain colonization by the bacterium, and damage from its gingipain enzymes, could contribute to Alzheimer’s-related pathology in at least some patients. The Science Advances paper said gingipains identified in Alzheimer’s brains correlated with tau and ubiquitin pathology. The authors presented that as evidence supporting further study of an infectious-disease pathway, but the paper did not establish that this mechanism explains Alzheimer’s disease broadly across patients. (pmc.ncbi.nlm.nih.gov) ### Was this evidence from people or from animals? The central findings behind the claim that COR388 reduced bacterial burden and amyloid-related pathology came from preclinical work, including mouse models, not from completed large human efficacy trials. Cortexyme later moved COR388, also known as atuzaginstat, into human testing through the GAIN Phase 2/3 study in mild to moderate Alzheimer’s disease. (pmc.ncbi.nlm.nih.gov) ClinicalTrials.gov describes GAIN as a randomized, double-blind, placebo-controlled trial testing two dose levels of COR388. Casey Lynch said in a July 28, 2020 company statement tied to the Alzheimer’s Association International Conference that atuzaginstat was being evaluated for its potential to slow or halt Alzheimer’s progression by blocking gingipains released by P. gingivalis. (science.org) That statement referred to preclinical presentations and phase 1b biomarker data, not a completed pivotal success in Alzheimer’s patients. ### What happened when the drug reached later-stage human testing? Cortexyme said in January 2022 that the U.S. (science.org) Food and Drug Administration had placed a full clinical hold on atuzaginstat’s investigational new drug application. BioPharma Dive reported the hold came after the drug had failed to show a benefit in a large trial of people with mild or moderate Alzheimer’s disease. The Alzheimer’s Drug Discovery Foundation report said small studies had hinted at benefit in some dementia patients but also cited serious hepatic safety concerns. The same report said there was little evidence that gingipain inhibitors were neuroprotective and that more data were needed. (biospace.com) ### So what should readers take from the “shows promise” claim? The strongest verified version of that claim is narrow. COR388 showed preclinical activity against a proposed bacterial pathway tied to Alzheimer’s disease, and the underlying papers reported reductions in P. gingivalis measures and amyloid-related pathology in animal models. (businesswire.com) The next step was always human proof. ClinicalTrials.gov records show Cortexyme advanced COR388 into the GAIN trial, and later company disclosures show the program ran into safety and development problems before establishing clear clinical benefit in Alzheimer’s patients. (clinicaltrials.gov) (science.org) (alzdiscovery.org)
