Amyloid theory sputters for AD

The amyloid hypothesis isn’t dead, but it seems to be limping a bit in the race for an Alzheimer’s cure.

Some researchers who predicted 5 years ago that an anti-amyloid disease-modifying therapy was imminent are now reevaluating that optimism — including the geneticist who first suggested the pathologic link between amyloid plaque deposition and Alzheimer’s disease.

“Everything is taking a lot longer than I thought it would; there’s no question about that,” he said.

A professor of neuroscience at University College London, postulated that b-amyloid deposition was the root of a pathologic cascade that resulted in Alzheimer’s disease. The concurrent discovery that a mutation in the amyloid precursor protein (APP) gene caused early-onset Alzheimer’s, coupled with the association of plaque deposition and early Alzheimer’s in Down syndrome patients, added weight to the theory. A new research boom was born.

But the first phase III trials of antiamyloid agents have brought no good news.

Tramiprosate, a b-amyloid antagonist, was the disappointment of 2007, tarenflurbil, a gamma-secretase modulator, this year’s downer. And positive findings in bapineurzumab’s phase II trial were slim. A post hoc analysis showed that some patients with mild to moderate Alzheimer’s, with no genetic risk factors, had cognitive improvement after getting the vaccine.

“The data right now are neither positive nor negative. At this point, the only thing we can say about bapineuzumab is that it’s not going to be a miracle therapy.”

A long-term follow-up study of patients enrolled in the early AN-1792 immunotherapy trial “doesn’t look great for amyloid, either.” The AN-1792 trial was halted early, in 2002, when some patients developed encephalitis after getting the vaccine. The follow-up showed that the vaccine did clear plaques, but that clearance didn’t affect cognition or survival. In fact, “seven of the eight immunized patients who underwent postmortem assessment, including those who virtually complete plaque removal, had severe and end-stage dementia before death.”

That slow progress on antiamyloid negates the theory’s basic truth, though — at least for a subset of patients. “There’s no doubt at all that the amyloid hypothesis explains the disease in families with mutations of the amyloid precursor protein and presenilin genes. A much more open debate is whether the same process is at work in the Alzheimer’s patient.”

But drug companies must target this larger population in order to create a financially successful therapy, and the lack of progress has them fidgeting. “Every drug company is worried and now wondering if they should widen to other therapies, including tau-targeted drugs. And to this I say, ‘Yes, of course you should have other strings for your bow.”

The essential mystery of amyloid further complicates things. “We don’t really know is amyloid as a function. It could be that amyloid is a response to vascular damage. We all ignore the fact that amyloid deposition occurs to a large extent to a vasculature . . . It could have something to do with vascular repair.”

That worry also plagues, a professor of pathology and Alzheimer’s researchers at Case Western Reserve University, Cleveland. “We have said for a long time that amyloid is doing something important in the brain. It could be acting like a vascular sealant in areas of injury. It forms structural scaffolding for blood vessels, and if you start getting rid of that scaffold, you’ll see problems in the blood-brain barrier.” This reaction probably caused the brain inflammation seen in the AN-1792 trial.

A consultant for several companies investigating non-amyloid-related therapies, is among a minority of researchers who resist the amyloid theory, although the overwhelming focus on amyloid has virtually drowned out their opinion. The amyloid research momentum is so strong right now that only more high-profile failures will begin to temper it, he said.

“People still can’t believe it’s not working, and they’re waiting for the results of the phase II vaccine trial,” as well as new data on b-secretase inhibitors, theorized to reduce the build-up of plaque-forming AB-42. “At this point, the research community is so totally invested in amyloid that we need to either get something else that works or have an honest, sober, the-party’s-over discussion of why amyloid-targeted therapies are failing.”

Director of the Alzheimer’s Disease and Memory Disorders Center at Baylor College of Medicine, Houston, has some ideas. The failure of antiamyloid drugs illustrates not a failure of the theory, but the failure of specific drugs and possibly of drug companies to follow a comprehensive and logical phase II plan.

“Companies want their drug to be labeled as a disease-modifying agent as soon as possible; the implication is that it can then be priced at a higher rate. And because they are going for that, they are designing phase II trials that are long and costly but don’t give them all the information they need.” 

Ideally, by the time any agent finishes phase II, there should be clear evidence that it is both safe and effective in the primary end point. “Neither tramiprosate nor tarenflurbil had a clear signal in phase II, and neither did bapineuzumab, although it at least had some signal. Another phase II study for bapineuzumab would have been nice to further clarify this proposed subpopulation of interest.”

Companies could also modify their research track to prove first that a drug confers symptomatic benefit, and then examine its possible disease-modifying properties. That is the path Medivation Inc. is following with dimebon — the only bright note in late-stage clinical trials this year. The antihistamine, thought to boost mitochondrial function, succeeded where the antiamyloids failed, significantly improving cognition, behavior, and function in Alzheimer’s patients, although it did not modify disease progression.

“Dimebon probably is a disease-modifying drug, but proving this requires long-term studies,” primary investigator on the phase II trial said. “But many pharmaceutical companies fear that a drug will be priced too low if they go for symptomatic approval first.”

Follows research on dozens of potential Alzheimer’s drug, only some of which are antiamyloids. But she agreed that these compounds grab the lion’s share the attention. “The amyloid story gets articulated over and over again because a lot of people in academia feel most comfortable with a story that’s already been told. But there’s no priori reason that any one of these approaches should work better than another.”

In fact, rather than a one-step cure, the compounds may be best used in primary prevention, the chief medical and scientific officer of Sun Health Research Institute, Sun City, Ariz., said. “The problem is, we may be approaching it too late.” “By the time you clinically manifest dementia, it might be too late for the drugs to help, even if they clear the plaques.

“The ideal future for an amyloid-based approach would probably be a combination of immunotherapy to break up existing plaques, and secretase inhibitors to prevent the formation of additional plaques,” an investigator on the phase II bapineuzimab trial said. Putting this to practical use will require big advancements in early detection.