The New England Journal of Medicine has publications from Pfizer / J&J and Lilly on their multiple phase III trials of anti-amyloid antibodies (bapineuzumab and solanezumab, respectively). As the world knows, neither of them hit their primary endpoints. How optimistic one can be after that is a matter for fine distinctions.
Medscape has a look-on-the-bright-side article here. There's some evidence that the antibodies were affecting amyloid, which is (presumably) at least a start:
. . .an analysis of apolipoprotein E (APOE) 4 carriers found a decreased rate of accumulation of amyloid in the brain in a subset of patients taking bapineuzumab who had positron emission tomography (PET) imaging using Pittsburgh compound B, although the difference was smaller than that seen in phase 2 studies using a higher dose of the drug. And, among carriers, bapineuzumab was associated with reduced concentrations of cerebrospinal fluid (CSF) phospho-tau, a marker of neurodegeneration.
"We were getting some target engagement and that's encouraging," said Dr. Salloway. "But we were limited in our ability to lower amyloid because of the dose-related side effects."
Those side effects were signs of edema in the brain imaging of the bapineuzumab patients who carried the APOE4 gene. Their dose was lowered to half a milligram per kilo, while the other patients got up to 1 mpk. The Phase II trials had gone up to 2 mpk, but that dose was dropped completely. At any rate, I think that bapineuzumab has also been dropped completely; I'm unaware of any further work with it. That's as opposed to solanezumab, where Lilly is famously pressing on.
It's at least better-tolerated than bapineuzumab, perhaps because it doesn't specifically target amyloid fibrils, but goes more after the soluble forms. And that, conceivably, is connected with the hints of efficacy that were seen in the patients with milder forms of Alzheimer's, and on this outcropping of solid bedrock rests Eli Lilly's Alzheimer's strategy. It's a tough place to be, but Lilly is already in a tough place, so a roll of the dice like this might be their best shot at this point.
There's a quote in the Medscape piece saying that we've "entered the era of prevention studies" in the disease, but that's too sunny even for an optimistic guy like me. We still have no clear idea of that actual early mechanisms that lead to Alzheimer's. The amyloid hypothesis, though it has a fair amount of evidence on its side, remains unproven, and every attempt to target it pharmacologically has either failed or (if you squint hard) just about failed. The only reason we're running prevention trials with the agents we have is that they failed to do anything in treatment trials. We have staggered into an era of prevention trials because we have nothing else to offer.
That doesn't mean I'm hoping for solanezumab or anything else to fail - far from it. A preventative agent for Alzheimer's would be a great advance. It's just that I'm not hopeful that any of the current therapies will work that way. If one does, it'll be a real long shot bet that's come through, and it's going to be five to ten years before we'll even know enough to say that. So I hope that I don't see too many "Alzheimer's Prevention Trials Underway!" headlines in the general press. The occasional mentions of a "cure by 2025" make a person wonder, though.
There's also a lot of talk about combination therapies, a monoclonal antibody, plus a secretase inhibitor, plus something for tau, and so on. That may well be the way to go, eventually. But it's worth remembering that previous cocktail regimens like this, in other disease areas, combined agents that showed much more robust effects than anything has in Alzheimer's so far. They were good enough, usually, to be approved on their own. In Alzheimer's, as it stands now, we'd be looking at combining two or three drugs that have all struck out in the clinic, and maybe one or two that we don't even have yet, and hoping for the best. I don't see that as a realistic strategy until something works a bit better. Or works at all.