How Azeliragon works
Azeliragon is a small molecule that inhibits a receptor protein that is thought to be involved in the development of Alzheimer’s disease, called the receptor for advanced glycation endproducts, or RAGE.
RAGE is a family of proteins present on the surface of several types of cells in the brain. It has several partner proteins, one of which is the advanced glycation endproduct (AGE). The accumulation of AGE in cells and tissues occurs naturally during aging but is accelerated in Alzheimer’s disease.
When AGE binds to RAGE, it triggers a state of inflammation that eventually leads to Alzheimer’s disease. This state of inflammation is characterized by blood vessel dysfunction, which promotes the transport of amyloid beta (Aβ), the main component of amyloid plaques found in the brain of Alzheimer’s disease patients, into the brain. It is also characterized by oxidative stress and an abnormal aggregation of a protein called tau in the form of filaments inside nerve cells, leading to their death.
Azeliragon binds to RAGE and prevents it from binding to its partner proteins and causing the inflammatory process that leads to Alzheimer’s disease.
Azeliragon in clinical trials
Initial Phase 2 clinical trials in patients with mild to moderate Alzheimer’s disease aimed to identify a safe, well-tolerated and effective dose of azeliragon.
One Phase 2 study found that 10 weeks of treatment with azeliragon was safe and well-tolerated in Alzheimer’s disease patients, indicating the feasibility of a larger trial.
A Phase 2b trial investigated the safety and effectiveness of azeliragon in 399 patients with mild to moderate Alzheimer’s disease. The results published in 2014 in the scientific journals BMC Neurology and Neurology showed that patients who received 5 mg of azeliragon a day for 18 months had a statistically significant benefit of 3.1 points in the Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-cog) compared to those who received a placebo.
Azeliragon at this dose also decreased the incidence of psychiatric adverse events and significantly decreased anxiety symptoms. Finally, the study demonstrated that 5 mg of azeliragon per day was more effective for mild than for moderate Alzheimer’s disease.
Based on these results, a Phase 3 trial (NCT02080364) called STEADFAST was initiated in 2015. This trial was designed to investigate the effectiveness of azeliragon in 800 patients with mild Alzheimer’s disease. Patients were recruited in 115 study locations worldwide. Each patient received either 5 mg per day of azeliragon or a placebo, each added to stable doses of an acetylcholinesterase inhibitor and/or memantine.
Patients were evaluated using the ADAS-cog or the Clinical Dementia Rating Scale Sum of Boxes (CDR-sb) after 18 months of treatment. The study is ongoing but no longer recruiting participants.
In 2016, an extension study of the STEADFAST trial was initiated (NCT02916056). In this Phase 3 trial, patients who completed the STEADFAST trial will receive azeliragon at 5 mg per day for up to two years. This study is currently recruiting participants at 57 study locations in the U.S. and Canada by invitation only.
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