This small-molecule investigational therapy grew out of the discovery that gingipains, cysteine proteases of the periodontal pathogen Porphyromonas gingivalis, penetrate gingival tissue and cause inflammation at the site of periodontisis (O'Brien-Simpson et al., 2009). Periodontitis has been linked epidemiologically to cognitive impairment and Alzheimer’s disease, and P. gingivalis bacterial lipopolysaccharide has been detected in postmortem brain tissue of people with AD (Poole et al., 2013). COR388 is an orally available inhibitor of gingipains.
Oral P. gingivalis infection was reported to worsen AD pathology and cognitive impairment in AD transgenic mice, and to cause neuroinflammation, memory impairment, neurodegeneration, micro- and astrogliosis, increased brain Aβ and phospho-tau, and neurofibrillary tangles in wild-type C57Bl6 mice (Ishida et al., 2017; Ilievski et al., 2018; Ding et al., 2018).
Cortexyme reported elevated gingipain in brain tissue from people with AD, and a correlation between levels of gingipain and tau proteins in postmortem middle temporal gyrus from AD and healthy control tissue. P. gingivalis DNA was detected in postmortem cortices from people with AD and healthy controls and in CSF of AD patients. In mice, oral P. gingivalis infection led to appearance of bacterial DNA in the brain, increased brain Aβ42 production, neuroinflammation, and hippocampal degeneration. The first three findings were reported to be reduced by COR388; results for hippocampal cell death were not reported (Jan 2019 news on Dominy et al., 2019).
As of June 2019, two Phase 1 trials of COR388 have been completed. In a single-dose study of 5 to 250 mg capsules in 34 healthy adults, the compound was safe and well-tolerated. A multiple-dose study assessed safety and tolerability in 24 healthy older adults (mean age of 60 years) and nine with AD (mean age 72). According to a company press release and poster presentation at CTAD 2018, healthy adults received 25, 50, or 100 mg COR388 or placebo every 12 hours for 10 days; AD patients took 50 mg or placebo every 12 hours for 28 days. The pharmacokinetic profiles of COR388 in AD and controls were reported to be similar. All volunteers with AD had P. gingivalis DNA fragments in their CSF at baseline. COR388 caused no serious adverse reactions, and no one withdrew.
A Phase 2/3 trial (GAIN) evaluating a 48-week course of COR388 in 573 people with mild to moderate AD began in April 2019. Participants take either 40 mg, 80 mg, or placebo. The primary endpoint will be ADAS-Cog11 score; further outcomes include ADCS-ADL, CDR-SB, MMSE, NPI, the Winterlight Speech Assessment, MRI brain scans, and P. gingivalis DNA measurement in CSF before and after treatment. This trial involves 32 sites in the U.S.; topline data are expected in late 2021.
For all trials of this compound, see clinicaltrials.gov.
Last Updated: 15 Dec 2019
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