In Alzheimer’s disease trial, atuzaginstat helps patients with severe gum disease
In a subgroup of patients with mild to moderate Alzheimer’s disease and showing signs of severe gum disease due to P. gingivalis infection, treatment with atuzaginstat (COR388) appeared to slow their cognitive decline, according to the results of the phase 2/3 GAIN clinical trial.
However, in all of the patients treated in the study, using atuzaginstat for approximately one year did not achieve this primary trial goal, or its other primary goal of improving activities. everyday. While all patients in the GAIN study showed signs of P. gingivalis infection in their cerebrospinal fluid, this subgroup of patients also had signs in their saliva, indicating a more serious infection.
“Evidence from the GAIN trial improves our ability to identify the right patients, impact an upstream target, and improve patient outcomes,” said Casey Lynch, CEO, Co-Founder and President of Cortexyme , which develops atuzaginstat, in a press release. Release.
Atuzaginstat is a small oral molecule that blocks the activity of gingipains, the toxic enzymes released by Porphyromonas gingivalis (P. gingivalis), a bacteria that causes gum disease, which has been linked to the development of Alzheimer’s disease.
The GAIN trial (NCT03823404) followed 643 adults, aged 55 to 80, with mild to moderate Alzheimer’s disease. Participants were randomized to receive 40 or 80 mg of atuzaginstat as an oral capsule, or a placebo, twice daily for 48 weeks (approximately one year). The main objective of the study was to assess the effect of treatment on standard measures of cognition and function of daily living.
Among all participants, atuzaginstat did not significantly improve cognition, as assessed by the Alzheimer’s Disease Rating Scale-Cognitive Sub-Scale 11 (ADAS-Cog 11), or ability of patients 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 The DNA in their saliva at the start of the study – indicating higher levels of infection with this bacteria – there was a dose response to atuzaginstat. A 57% slowdown in cognitive decline was observed in the 80 mg group and a 42% slowdown in the 40 mg group, compared to those on placebo.
No significant benefit in terms of function of daily living, as assessed by the ADCS-ADL scale, was observed in this subgroup of patients.
Reductions of P. gingivalis found in patients’ saliva at week 24 were also significantly correlated with improved cognitive outcomes at week 48 (end of treatment), and a beneficial trend was observed in function, although this was not statistically significant.
A trial substudy also looked at the effects of atuzaginstat on symptoms of gum disease, including the depth of gum pockets. The results here showed a trend towards a pocket depth benefit in the 242 patients with P. gingivalis DNA detectable in saliva.
The side effects reported were mild to moderate in severity, the most common being gastrointestinal, such as diarrhea and nausea. Atuzaginstat was also associated with dose-dependent elevations in liver enzymes, but these were not clinically significant.
“The P. gingivalis– the infected participating population was easily identified with saliva or simple blood tests and was very responsive to atuzaginstat treatment on several clinical measures, and we will quickly discuss next steps with global regulators, ”said Michael Detke , MD, PhD, Medical Director of Cortexyme.
“The first large clinical study of a gingipain inhibitor confirmed the benefits of treatment in the appropriate population at doses that reduce P. gingivalis. The modification of disease and the preservation of cognition, as demonstrated in the GAIN trial, form the basis for modifying the course of Alzheimer’s disease, ”added Detke. “We are grateful to the participants, caregivers and researchers for their participation and dedication to this important study. “
Additional trial results are expected to be announced at the 14th Alzheimer’s Disease Clinical Trials Conference (CTAD 2021) on November 11.