The Phase II/III GAIN trial (NCT03823404) of novel small molecule gingipain inhibitor atuzaginstat (COR388) for the treatment of mild-moderate Alzheimer’s disease is based on the gingipain hypothesis, which states that P. gingivalis found in the brain of Alzheimer’s patients secretes gingipain proteases that promote neuronal damage. The GAIN trial randomized over 640 patients to receive low- or high-dose atuzaginstat or placebo, assessing ADAS-Cog 11 and ADCS-ADL as co-primary endpoints. In the overall intention-to-treat population, there was no significant difference in these measures between the treatment and placebo arms, but a statistically significant slowing of cognitive decline (30-50%) was seen in the treatment arms in patients with higher infection levels, measured by P. gingivalis DNA levels in saliva. New target engagement and biomarker data presented at AD/PD 2022 supports the continued development of atuzaginstat. Evidence of Kgp inhibition, an activity-based probe specific for the active site of the gingipain, supports that atuzaginstat engaged the target, inhibiting lysine gingipains. Trends towards benefit were seen in cerebrospinal fluid (CSF) biomarkers, as well as MRI brain volumetric measures, in the atuzaginstat arms. These brain volumetric measures also showed correlation with the clinical co-primary endpoints ADAS-Cog11 and ADCS-ADL, implicating P. gingivalis in disease progression. This interview took place at the AD/PD™ 2022 Conference in Barcelona, Spain.
