Alzheimer’s disease and P. gingivalis infection in phase II/III GAIN trial: additional top-line data with atuzaginstat presented at CTAD 2021.-Cortexyme, Inc.

The presentation will expand on previously reported top-line results that demonstrated the relationship between the reduction of Porphyromonas gingivalis (P. gingivalis) infection and the slowing of cognitive decline in Alzheimer’s disease with atuzaginstat treatment in a prespecified population of patients based on diagnosis of infection.

The 643-participant 48-week GAIN Trial was the first large study to test the efficacy of an oral small-molecule targeting P. gingivalis for disease modification in mild to moderate Alzheimer’s patients. While not meeting statistical significance on its co-primary cognitive and functional endpoints in the overall cohort, the study data showed that treatment with atuzaginstat slowed decline compared to placebo on the majority of clinical endpoints in prespecified populations that were selected based on P. gingivalis infection markers.

The GAIN Trial results showed that the 40 mg BID arm demonstrated equivalent or better efficacy across key endpoints compared to the higher dose, 80 mg BID, as well as a superior safety profile. Trends to benefit at 40 mg BID were seen with multiple prespecified analytic approaches, including on ADAS-Cog11, CDR-SB, MMSE, and NPI, with increasing separation from placebo throughout the study consistent with disease modification. Benefits were not seen on ADCS-ADL at either dose.

Changes in P. gingivalis DNA levels in saliva correlated significantly with clinical outcomes during and at the end of treatment, demonstrating that reduced P. gingivalis bacterial load resulted in better clinical outcomes. A trend to slowing of the primary biomarker endpoint of hippocampal atrophy was seen in treatment groups, but did not reach significance.

" The GAIN Trial achieved several significant advancements for the Alzheimer’s field, first by clinically confirming that P. gingivalis is a key upstream driver of disease progression. Further, the data demonstrated a compelling risk-benefit profile with a clinically significant treatment response in an easily identifiable population of patients,” said Marwan Sabbagh, MD, FAAN, lead investigator of the GAIN Trial and Professor of Neurology at the Barrow Neurological Institute. “I am particularly encouraged by GAIN’s identification of a target population, which is consistent with the heterogeneous nature of Alzheimer’s disease and comparable to treatment advancements based on diagnosis of infectious disease, like HIV dementia and personalized medicine common in other therapeutic areas, like oncology. When coupled with the convenience of oral dosing, atuzaginstat offers the potential to fill a huge gap in the underserved mild to moderate Alzheimer’s population in as many as half of those patients. I was gratified to act as the lead investigator for this important study that will hopefully be part of our arsenal of treatments for Alzheimer’s in the not-so-distant future.”.

Cortexyme plans a new study to test whether the GAIN trial positive sub group effect was representative of a real treatment benefit for mild-to-moderate Alzheimer's patients. Cortexyme is most likely to select the lower of two doses that it used in the failed trial, as the higher dose was more frequently associated with side effects, particularly those indicating liver damage.