Alzheimer's disease certainly has an inflammatory component to it, as do other neurodegenerative conditions. The immune system of the brain runs awry in characteristic ways. Evidence exists to suggest that short-lived advanced glycation end products (AGEs) of the sort found in individuals with metabolic syndrome and type 2 diabetes are a significant source of inflammation. They act via the receptor for AGEs, RAGE. This, I should note, is entirely unrelated to the detrimental effects of persistent, long-lived AGEs on tissue structure. Short-lived AGEs are more of a lifestyle issue, in that everyone has them to some degree, but they are strongly associated with diet, obesity, and the metabolic diseases of obesity.
In any case, some effort has gone into building ways to interfere in RAGE-induced inflammation, and one of them made it as far as clinical trials for Alzheimer's disease. Unfortunately it joins the sizable and growing pyre of failed trials for this condition - and by the look of it was running largely on hope for much of its lifetime, one of many things wrong with the present system of trials and its dominant focus on marginal effects. It is possible that reducing inflammation simply isn't enough on its own, given everything else that is going on in the Alzheimer's brain, or that RAGE is not an important source of inflammation in comparison to others in Alzheimer's patients, or the effects did not translate well from animal studies.
Yesterday, vTv Therapeutics announced the termination of both parts of its STEADFAST clinical study, which had been testing the small molecule azeliragon in patients with probable Alzheimer's. According to data from the Phase 3 clinical trial, patients who took the drug for 18 months performed no better than those on placebo in tests of cognition and function. Though only a fraction of patients in Part B, which is identical in design, have completed 12 months on the drug, the company has terminated that trial.
Azeliragon blocks the receptor for advanced glycation end products (RAGE), which can cause inflammation in the brain. Because microglia and astrocytes upregulate expression of RAGE in AD, and because evidence suggested RAGE binds and mediates Aβ toxicity, researchers reasoned that blocking the receptor would be beneficial. TransTech Pharma discovered azeliragon, a.k.a. TTP 488, and licensed it to Pfizer, which, together with the National Institute on Aging, sponsored an 18-month trial of the antagonist back in 2007. Run by the Alzheimer's Disease Cooperative Study, it tested daily doses of 5 mg and 20 mg given after six-day ramp-ups of 15 mg and 60 mg, respectively, in patients with mild to moderate AD. Trials of both dosing regimens were halted early for lack of efficacy.
Latching onto hints of a benefit in patients with mild AD, TransTech Pharma, which would become vTv, received fast-track approval from the Food and Drug Administration to test the drug in patients with probable AD and a brain MRI consistent with that diagnosis. No other markers were used for inclusion criteria. The STEADFAST study was slated to recruit 800 participants randomized to either 5 mg/day azeliragon or placebo.
Link: https://www.alzforum...isease-patients
View the full article at FightAging
