Atuzaginstat Slows Cognitive Decline in P. Gingivalis-Positive Participants

In the phase 2/3 GAIN trial (NCT03823404), across all participants (n=643) with mild to moderate Alzheimer disease (AD) treated with atuzaginstat (COR338; Cortexyme, South San Francisco, CA), no statistically significant effect on cognition and function was seen. Atuzaginstat is an investigational orally administered small molecule that targets gingipain proteases from the bacterium Porphyromonas gingivalis (P. gingivalis), the bacteria that causes gum disease.

In a prespecified subgroup of participants with P. gingivalis DNA in their saliva at baseline (PG-DS; n=242), however, there was a dose-responsive effect on cognition. Participants treated with 80 mg or 40 mg atuzaginstat, respectively, had 57% (P=.02) and 42% (P=.007) slowing of cognitive decline.

Participants who had reductions in P. gingivalis in saliva at week 24 were more likely to have improved cognitive outcomes at the end of the treatment period as measured by the AD Assessment Scale-Cognitive Subscale (ADAS-Cog11) (P=.0007), Clinical Dementia Rating–Sum of Boxes (CDR) (P=.004), and Mini-Mental State Exam (MMSE) (P=.007). There was a trend of improvement on activities of daily living as measured with the AD Cooperative Study Activity in Daily Living (ADCS-ADL) scale that was not statistically significant (P=.08).
 
“The first large clinical study of a gingipain inhibitor confirmed the benefits of treatment in the appropriate population at doses that reduce P. gingivalis. Disease modification and preservation of cognition as demonstrated in the GAIN Trial provides the foundation for altering the course of Alzheimer,” said Michael Detke, MD, PhD, Cortexyme’s chief medical officer. “The P. gingivalis-infected participant population was easily identified with saliva or simple blood tests and was highly responsive to atuzaginstat treatment on multiple clinical measures, and we will be discussing next steps with global regulators promptly. We are grateful to the participants, caregivers, and investigators for their participation and dedication to this important study.”
 
The most common adverse events were mild to moderate in severity, such as diarrhea (16%) and nausea (6%) in participants treated with atuzaginstat vs 3% and 2% of participants treated with placebo, respectively.