Atuzaginstat Shows Potential in GAIN Trial Patients With Severe Gum Disease
In a subset of patients with mild to moderate Alzheimer’s and evidence of severe gum disease due to P. gingivalis infection, treatment with atuzaginstat (COR388) appeared to slow their cognitive decline, according to results from the Phase 2/3 GAIN clinical trial.
Across all treated study patients, however, atuzaginstat’s use over about one year failed to meet this primary trial goal, or its other main goal, that of improving daily life activities. While all patients in the GAIN study showed evidence of P. gingivalis infection in their cerebrospinal fluid, this patient subgroup had evidence in their saliva as well, indicating a more severe infection.
“The evidence from the GAIN Trial advances our ability to identify the right patients, impact an upstream target, and improve patient outcomes,” Casey Lynch, CEO, co-founder, and chair of Cortexyme, which is developing atuzaginstat, said in a press release.
Atuzaginstat is an oral small molecule that works to block the activity of gingipains — the toxic enzymes released by Porphyromonas gingivalis (P. gingivalis), a bacteria responsible for gum disease, that have been linked with Alzheimer’s development.
The GAIN trial (NCT03823404) followed 643 adults, ages 55 to 80, with mild to moderate Alzheimer’s. Participants were randomized to either 40 or 80 mg of atuzaginstat as an oral capsule, or to a placebo, twice daily for 48 weeks (about a year). The study’s main goal was to evaluate the treatment’s effect on standard measures of cognition and daily life function.
Across all those enrolled, atuzaginstat did not significantly improve cognition, as assessed by the Alzheimer’s Disease Assessment Scale-Cognitive Subscale 11 (ADAS-Cog 11), or patients’ ability to function, measured using the Alzheimer’s Disease Cooperative Study Group-Activities of Daily Living (ADCS-ADL).
However, among the 242 patients with detectable levels of P.gingivalis DNA in their saliva at the study’s beginning — indicating higher levels of infection by this bacteria — there was a dose response to atuzaginstat. A 57% slowing of cognitive decline was seen in the 80 mg group and a 42% slowing in the 40 mg group, compared with those on placebo.
No significant benefits in terms of daily life function, as assessed by the ADCS-ADL scale, was seen in this patient subgroup.
Reductions in P. gingivalis found in patients’ saliva at week 24 also significantly correlated with improved outcomes in cognition at week 48 (end of the treatment) , and a beneficial trend was seen in function, although this was not statistically significant.
A trial sub-study also looked at the effects of atuzaginstat on symptoms of gum disease, including the depth of gingival pockets. Results here showed a trend toward benefit on pocket depth in the 242 patients with P. gingivalis DNA detectable in saliva.
Adverse events were reported to be mild to moderate in severity, with the most common being gastrointestinal, such as diarrhea and nausea. Atuzaginstat was also associated with dose-related elevations in liver enzymes, but these were not clinically significant.
“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,” said Michael Detke, MD, PhD, Cortexyme’s chief medical officer.
“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’s,” Detke added. “We are grateful to the participants, caregivers, and investigators for their participation and dedication to this important study.”
Additional trial results are set be announced at the 14th Clinical Trials on Alzheimer’s Disease (CTAD 2021) conference on Nov. 11.