A Failure to Treat Alzheimer's by Interfering in RAGE-Induced Inflammation

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 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.org/news/research-news/fighting-rage-no-help-alzheimers-disease-patients


Why did blocking rage fail? Do they have any theories?

Posted by: Nathan at April 13th, 2018 7:43 AM

Too little, too late (emphasis on too late) perhaps?
Angiotensin receptor blockers are supposed to suppress RAGE production and their use is associated with reduced rates of dementia, IIRC.

Posted by: CD at April 13th, 2018 10:00 AM

We just can't put a dent in this thing can we?

Many are of the belief that we are starting treatment too late.

Reason is right about the flaws of current trial methodology.

Starting treatment earlier will probably help, but conducting trials would be very time consuming, and we simply don't have the window of time needed to prevent or mitigate the horrendous costs associated with this disease as the population ages.

This isn't looking good.

Posted by: Mark Borbely at April 13th, 2018 10:54 AM

@Mark: My guess is that companies keep failing because they don't attack A-beta and tau at the same time, only one of them. AD clearly has multiple causes, and you can't win by only addressing one of them. Maybe inflammation must be addressed too, but you can start with A-beta+tau and see what happens, instead of hitting always the same walls.

Posted by: Antonio at April 13th, 2018 6:31 PM

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