Present clinical data supporting the gingipain hypothesis of AD.

Porphyromonas gingivalis (Pg) has been discovered in the brain and cerebral spinal fluid of AD patients, along with its toxic virulence factors called gingipains. Oral infection of mice with Pg resulted in brain colonization, increased production of Aβ1-42, detrimental effects on tau and loss of hippocampal neurons. Cortexyme invented small-molecule gingipain inhibitors to block this neurotoxicity and COR388 was selected to progress to human trials.

A Phase 1b study included a cohort of AD subjects 55-85 with baseline MMSE between 14 and 25, that received 50 mg of COR388 or placebo q12h for 28 days as outpatients. 6 received COR388 and 3 received placebo.

COR388 was safe and well tolerated in this study. Adverse events were infrequent, transient, and mild-moderate in severity. No clinically significant trends were seen in laboratory values or ECGs.

P. gingivalis DNA fragments were detected in the CSF of 9 out of 9 AD subjects analyzed by PCR.  There were statistically significant reductions in the inflammatory marker RANTES and ApoE fragments in the subjects treated with COR388 vs. placebo. 

MMSE and CANTAB scores showed numerical trends of improvement for COR388 compared to placebo.  Winterlight’s speech and cognitive battery revealed statistically significant improvements in the COR388 group vs. placebo in total content units, total number of objects and use of prepositions and subordinating conjunctions.

COR388 is a promising drug for the treatment of AD with a novel mechanism of action. COR388 was safe and well tolerated in Phase 1. There were significant improvements in mechanistically relevant biomarkers, there were trends of improvement in some cognitive, and significant improvement in language tests. Based on these data, Cortexyme initiated the phase 2/3 GAIN trial of COR388 in mild to moderate AD in 2019.