Data from a Phase 2b clinical trial showing that vTv Therapeutics‘s investigational drug, azeliragon, slows cognitive decline in patients with mild Alzheimer’s disease were presented at the Alzheimer’s Association International Conference 2016 in Toronto this week.
Azeliragon is a drug that blocks the receptor RAGE (Receptor for Advanced Glycation Endproducts) in the brain. Normally found in low numbers in a healthy brain, RAGE numbers increase during inflammation.
Examinations of deceased Alzheimer’s patients indicate that RAGE numbers seem to correlate with disease severity and progression. The higher number affects both neurons and glial cells in the brain, and is linked to blood vessel dysfunction — another key factor that influences dementia development.
Preclinial studies have shown that blocking the receptor impacts several processes that researchers believe contribute to Alzheimer’s disease. It reduces the accumulation of amyloid-beta and prevents the formation of fibrils made up of the tau protein. Azeliragon also dampens brain inflammation.
The study compared azeliragon to placebo in a randomized, double-blind manner — with neither patient nor study staff aware of which treatment a patient received. Evaluated were 399 patients with mild to moderate Alzheimer’s disease, who had been treated with cholinesterase inhibitors or Namenda (memantine).
The trial initially explored two dosing strategies. The higher dosing regimen was initiated with 60 mg azeliragon per day for six days, followed by a maintenance dose of 20 mg per day for 18 months. Patients receiving the lower dose started with 15 mg per day for six days, followed by 5 mg a day for 18 months. (The higher dose was discontinued because of side effects, including signs of increased confusion and a larger risk for falls compared to the placebo group.) The lower-dose group continued for a longer period.
At study start, participant cognition was evaluated using the standardized tool ADAS-Cog11 for measuring dementia changes. Initial analyses showed that patients in the different groups, at study start, did not differ in the severity of dementia or age. After 18 months of treatment, patient cognition was again evaluated, and found that those receiving azeliragon 5 mg a day had a lower rate of decline, with an average decline score of 3.1 less than placebo-treated individuals.
Further analyses showed that the change in decline was larger in patients with mild disease, who deteriorated an average of 4 points less than placebo-treated patients. Considering the time it took for patients to experience cognitive deterioration — which in the study was defined as an increase of seven points on the dementia severity measurement — the treatment was seen to benefit patients with mild Alzheimer’s disease, who started experiencing a lower rate of decline after nine months of treatment.
“Azeliragon is the only treatment in advanced development that works by inhibiting RAGE, which is believed to promote Aβ accumulation, tau hyperphosphorylation and chronic inflammation, the leading pathologies in Alzheimer’s disease,” said Dr. Larry Altstiel, vTv Therapeutics’ chief medical officer, in a news release.
Altstiel pointed out that the results support the design of the current Phase 3 trial of azeliragon in the STEADFAST study (NCT02080364), evaluating the treatment in patients with mild Alzheimer’s disease. As previously reported in Alzheimer’s News Today, the STEADFAST trial, involving 91 study centers across the U.S. and Canada, is currently recruiting participants. For more information about the study, including locations and contact information, see the trial website at clinicaltrials.gov.