Phase 2 Study of Atuzaginstat Identifies Population of P. Gingivalis Positive Individuals With Alzheimer Disease Responsive to Treatment
The phase 2/3 GAIN study (NCT03823404), has identified a therapeutic dose of atuzaginstat (Cortexyme, South San Francisco, CA) for potential treatment of Alzheimer disease (AD) in a specific target population of people with AD who are positive for P. gingivalis infection. The bacteria P. gingivalis, which causes gum disease, is ubiquitous, affecting over 65 million people in the US.
Although atuzaginstat did not meet statistical significance on primary outcome measures across the entire trial population (n=643), analysis of the prespecified P. gingivalis positive subgroup showed benefits on cognition and neuropsychiatric symptoms compared with P. gingivalis negative participants and those treated with placebo. Lowering of P. gingivalis DNA levels in saliva correlated significantly with clinical outcomes during and at the end of treatment.
Both efficacy and tolerability were higher among individuals treated with the lower 40 mg twice-daily dose of atuzaginstat compared with 80 mg twice daily. Cognitive benefits were seen on the Alzheimer Disease Assessment Scale 11 (ADAS-Cog11), Clinical Dementia Ratting scale Sum of Boxes (CDR-SB) and Mini Mental State Examination (MMSE). Neuropsychiatric benefits were measured with the Neuropsychiatric Inventory (NPI). No improvement in the Alzheimer Disease Cooperative Study Activities of Daily Living (ADCS-ADL) scale were seen.
“Our ability to identify the right population in historically hard to treat mild-to-moderate AD, along with finding an efficacious dose with a differentiated safety profile, is important progress toward a breakthrough treatment for AD,” said Michael Detke, MD, PhD, Cortexyme’s chief medical officer. “We saw clinically significant effects ranging from 30% to 50% slowing on ADAS-Cog11 and CDR-SB measures. . . and we look forward to sharing additional study data as it becomes available over the coming months.”
Marwan Sabbagh, MD, FAAN, lead investigator of the GAIN Trial and Professor of Neurology at the Barrow Neurological Institute said, “I am particularly encouraged by GAIN’s identification of a target population, which is consistent with the heterogeneous nature of AD 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 population with mild-to-moderate AD in as many as half of those patients.”
Rates of adverse events (AEs) were similar in those treated with 40 mg atuzaginstat twice daily or placebo. Most AEs were mild-to-moderate in severity and included diarrhea and nausea. Dose-related liver enzyme elevations occurred with atuzaginstat that were not clinically significant and resolved. There were 2 participants treated with 80 mg atuzaginstat twice daily who had concomitant bilirubin elevations without alternative explanation. No increase in amyloid-related imaging abnormalities (ARIA) were seen.