How azeliragon works
Azeliragon is a small molecule that inhibits a receptor protein 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 cell types in the brain. It has many 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 is thought to eventually lead 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 brains 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 showed an improvement 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 clinical 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 at 115 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.
In 2016, an extension study (NCT02916056) of the STEADFAST trial was initiated. In this Phase 3 trial, patients who completed the STEADFAST trial would receive azeliragon at 5 mg per day for up to two years.
In April 2018, vTv Therapeutics announced the termination of both the STEADFAST and STEADFAST extension trials. The STEADFAST trial failed to show a statistically significant difference between treatment and placebo groups in either of its primary endpoints, ADAS-cog and clinical dementia rating scale sum of boxes (CDR-sb). With the failure of the STEADFAST trial, the extension trial was also terminated before reaching full recruitment.
After further analysis of subgroups of STEADFAST patients, vTv Therapeutics presented data in March 2019 showing a decrease in cognitive decline, dementia, and inflammation in patients with mild Alzheimer’s disease and type 2 diabetes. The presentation was given at the 14th International Conference on Alzheimer’s and Parkinson’s Diseases.
Following these results, a new Phase 2/3 trial (NCT03980730) was initiated in June 2019. This study will investigate the safety and efficacy of azeliragon in patients with mild Alzheimer’s disease and impaired glucose tolerance (diabetes). The Phase 2 part of the trial aims to enroll approximately 100 patients. Half will receive 5 mg of azeliragon and the other half will receive a placebo. It is expected that this part of the trial will last six months. Then, if the results are successful, another 200 patients will be enrolled for the Phase 3 portion of the trial, which will last 18 months.
Both phases of the trial will look at changes from baseline in the 14-item ADAS-cognitive subscale (ADAS-cog14). The Phase 3 portion of the study will assess the CDR-sb scores as well. vTv expects results from the first portion of the trial at the end of 2020, with completion of the full trial in July 2023. The trial is currently recruiting participants in the United States and Canada.
Last updated: Aug. 18, 2019
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