Cortexyme Inc., reports GAIN trial data of atuzaginstat demonstrated relationship between reduction of P. gingivalis infection and slowing of Alzheimer’s disease progression.

The 643-participant study in mild to moderate patients with Alzheimer’s disease did not meet statistical significance in its co-primary cognitive and functional endpoints as measured by ADAS-Cog11 and ADCS-ADL at end of the treatment period in the overall cohort.The pre-specified subgroup of participants with P. gingivalis DNA detectable in saliva at baseline (PG-DS; n=242) showed a dose response, with a 57% slowing of cognitive decline as measured by ADAS-Cog11 in the 80 mg BID arm (p=0.02) and a 42% slowing in the 40 mg BID arm (p=0.07) vs. placebo. Significant benefits in this subgroup were not seen on the other co-primary, ADCS-ADL.

The cognitive benefit of atuzaginstat in patients with high P. gingivalis infection was reinforced by similar results in multiple pre-specified infection related subgroups and with multiple methods of analysis. Additionally, reductions in P. gingivalis in saliva at week 24 were significantly correlated with improved outcomes at the end of the treatment period as measured by ADAS-Cog11 (p=0.0007), Clinical Dementia Rating–Sum of Boxes (CDR) (p=0.004), Mini-Mental State Exam (MMSE) (p=0.007), and a beneficial trend on ADCS-ADL (p=0.08).

The sub-study in periodontal disease demonstrated a trend to benefit on the primary clinical endpoint of pocket depth in the same pre-specified sub-group with P. gingivalis DNA detectable in saliva. Further results will inform the next stage of development in periodontitis and will be presented at a future scientific conference.

“Today marks a major milestone toward a comprehensive understanding of Alzheimer’s and slowing of disease progression. The evidence from the GAIN Trial advances our ability to identify the right patients, impact an upstream target, and improve patient outcomes,” said Casey Lynch, Cortexyme’s chief executive officer, co-founder, and chair. “We are focused on next steps to advance this breakthrough treatment for the benefit of patients and their families.

Most adverse events were mild to moderate in severity. The most common were gastrointestinal, such as diarrhea in up to 16% and nausea in 6% of participants treated with atuzaginstat vs. 3% and 2% of placebo participants, respectively. Atuzaginstat was associated with dose-related liver enzyme elevations greater than 3X the upper limit of normal: 2% on placebo, 7% on 40 mg BID, and 15% on 80 mg BID. These elevations alone were not clinically significant, and virtually all participants were asymptomatic. Two participants in the 80 mg BID arm had concomitant bilirubin elevations without alternative explanation. Lab changes resolved while participants remained on drug or after withdrawal without any known long-term adverse effects. Atuzaginstat treated groups showed no increase in ARIA (amyloid-related imaging abnormalities), including microhemorrhage and edema, or superficial siderosis.