The investigational therapy azeliragon decreased inflammation and lessened cognitive decline and dementia in patients with mild Alzheimer’s disease and type 2 diabetes, compared with a placebo, according to data from a subgroup analysis of the Phase 3 STEADFAST study.
The findings were described in the presentation, “Inflammatory Biomarkers, Brain Volumetric MRI, FDG-PET results in Patients with Diabetes in Azeliragon Phase 3 trial in mild Alzheimer’s Disease,” during the 14th International Conference on Alzheimer’s and Parkinson’s Diseases and related neurological disorders, March 26-31, in Lisbon, Portugal.
Previous studies have found that people with type 2 diabetes are more likely to develop Alzheimer’s disease. There are more than 400 million people with diabetes around the world who are at a higher risk of developing dementia.
Azeliragon is a small investigational molecule, developed by vTv Therapeutics, that inhibits a receptor protein thought to be involved in the development of Alzheimer’s, called the receptor for advanced glycation endproducts, or RAGE.
Binding of RAGE to its partner proteins, such as the advanced glycation endproduct (AGE), triggers a state of inflammation that can eventually lead to Alzheimer’s disease. Azeliragon binds to RAGE and prevents it from binding to these other proteins, and in this way, halts the underlying inflammatory process.
The Phase 3 STEADFAST (NCT02080364) study — two independent and identical placebo-controlled Phase 3 trials (A-Study and B-Study) — assessed the efficacy and safety of azeliragon to treat mild Alzheimer’s disease. Topline results announced back in 2018 revealed that the A-Study and the B-Study did not meet primary goals — improvements in cognition — and the clinical trials were stopped. However, subsequent post-hoc subgroup analyses have shown that certain groups experienced positive benefits.
AChE inhibitors target the acetylcholinesterase enzyme, preventing it from breaking down acetylcholine, and cause an increase in the level and duration of the neurotransmitter’s acetylcholine activity. AChEs have been found to be an effective therapy for Alzheimer’s patients.
Participants were randomized to either 5 mg of azeliragon treatment or a placebo (sugar pill) taken orally once daily for 18 months. The therapy’s effectiveness was assessed using specific cognitive tests.
The study included a subgroup of Alzheimer’s patients with type 2 diabetes, as shown by a haemoglobin A1c (HbA1c) levels of 6.5% or higher at the start of the trial. HbA1c stands for glycated haemoglobin, and measures the levels of hemoglobin within red blood cells that gets attached to a sugar (glucose).
During the trial, the researchers measured the levels of RAGE-related biomarkers in the blood. Additionally, they evaluated patients’ brain volume using magnetic resonance imaging (MRI), both at the start of the trial and after 18 months.
The team also measured the brain’s metabolic activity using fluorodeoxyglucose positron emission tomography (FDG-PET) at the start of the trial and after 12 months and 18 months. In this imaging technique, FDG, a radioactive glucose compound, is injected directly into the blood. PET scans then measure the uptake of FDG in brain cells, which is an indicator of metabolic activity.
In total, the STEADFAST study recruited 56 patients with both Alzheimer’s and type 2 diabetes — 23 patients were randomized to the placebo group and 33 to the azeliragon treatment group. The clinical characteristics between the two groups were similar at the beginning of the trial.
The brain MRI and FDG-PET data showed a favorable trend for lower brain shrinkage, and the chambers within the brain that contain the cerebrospinal fluid (CSF) — called ventricles — were less enlarged in patients treated with azeliragon.
The uptake of the radiotracer in the FDG-PET scan showed that the metabolic activity of nerve cells in several regions in the brain was better preserved in patients treated with azeliragon.
Treatment also led to a decrease in inflammatory biomarkers associated with RAGE activation, including interleukin (IL)-6, IL-12, interferon-gamma, among others.
These results add to previous data that showed azeliragon in Alzheimer’s patients with diabetes led to a statistically significant benefit of 3.5 points in the Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-cog) and of 0.7 points in the Clinical Dementia Rating Scale Sum of Boxes (CDR-sb, a scale for assessing dementia severity) compared with a placebo.
vTv is planning a follow-up study on mild Alzheimer’s disease patients with diabetes to further evaluate azeliragon’s effect on cognition.