Alzheimer’s researchers – and their patients – just can’t seem to catch a break. While many fields of medicine are marching to an increasingly upbeat drummer, the AD parade just keeps getting rainier and rainier.
The latest downer was semagacestat, a gamma secretase inhibitor whose encouraging 2008 debut didn’t pan out. Last week, in the midst of the drug’s twin phase III studies, developer Eli Lilly pulled the plug – and more hope swirled down the drain.
The preplanned interim analysis was a bummer on several fronts. Not only did patients getting the drug fail to improve – they actually got worse than the placebo group, both cognitively and functionally. Adding injury to insult, the semagacestat group also began to develop incident skin cancers, probably a by-product of the drug’s interference with Notch signaling.
Gamma secretase inhibitors decrease the type of beta amyloid that clumps into Alzheimer’s brain plaques by changing the protein’s molecular length into a less toxic form. These drugs also interfere with Notch signaling, a process important in programmed cell death. Blocking it particularly affects organ systems with high cell turnover, such as the gut and immune system – one reason gamma secretase drugs have floundered in research. Many patients can’t tolerate the GI side effects.
But apparently Notch interference also bulks up the risk of skin malignancy. Mice bred to express impaired Notch signaling develop hyperplastic epidermis, cutaneous squamous cell carcinoma, and actinic keratoses (Cancer Res 2006;66:7438-44).
The semagacestat story also implies that the long-accepted amyloid theory of Alzheimer’s disease may not be the be-all and end-all of therapeutic targets. A decade of research has focused on getting rid of amyloid – in the brain, in the blood, in the cerebrospinal fluid. And yet not a single antiamyloid drug has come to fruition. In phase II, semagacestat did decrease the toxic Aβ40-42 in blood, proving that it does affect the protein’s formation. But that finding didn’t translate into any clinical benefit.
So what does that all mean? Probably that, just like you can’t fix cardiac muscle damaged by infarct, you can’t fix Alzheimer’s brain damaged by amyloid plaques. Probably that, like effective cardiovascular therapy, effective Alzheimer’s therapy needs to start at the very onset of symptoms, or even before symptoms are apparent.
The disease’s hottest research track right now is how to back up this diagnostic timeline by detecting amyloid in the brain and in blood and CSF. Once neurologists can identify patients before they become patients –when they are simply trying to remember where they put the car keys – it might be time to take some of these “failed” drugs out of mothballs and see how they perform at the starting gate, rather than the finish line.
– Michele G. Sullivan (on Twitter @MGsullivan)