Back in December, I wrote about the (as yet unexplained) findings of brain shrinkage in patients treated with anti-amyloid antibodies. Those, of course, have had a tremendous amount of press in the last few months, and those, of course, are proposed as therapies for Alzheimer’s, and brain shrinkage (of course) would seem to be one of the last things you’d want to induce in that situation.
Here’s a new analysis of the situation (and here’s more coverage here at Science). It illustrates that the problem is not just with antibody-based therapies – trials of secretase inhibitors showed a notable shrinkage in the hippocampus, for example (the very brain structure known to be involved in many aspects of memory). But the antibody trials show unmistakeable signs across the entire brain, and there seems to be a real correlation between the amount of ventricular enlargement (that is, the increase in empty space) and the amount of ARIA (amyloid-related imaging abnormalities) brought on by the antibody treatment.
I was not happy about all this when I wrote that post in December, and I’m even less happy to read this new analysis. Here’s the bottom line from it: “Mild Cognitively Impaired participants treated with anti-Aβ drugs were projected to have a material regression toward brain volumes typical of Alzheimer’s dementia ∼8 months earlier than if they were untreated.” I would say that if someone wants to make the argument that this is of no consequence (or perhaps even beneficial?) that they should step right up and have a crack at it. I (and many others) will watch with great interest. On the other hand, if the way of dealing with these findings is to pretend that they don’t exist, that is really unacceptable.
One of the authors of the new paper told Science that “I find it very peculiar that these data, which are very important, have been completely ignored by the field”. I know where he’s coming from, but I think the explanation is that people just don’t want to hear about it. The companies involved want to have an Alzheimer’s breakthrough and want to get the first new drug in many years for the disease onto the market in a relatively unencumbered way. Alzheimer’s patients and their families desperately want to hear that there is something that can be done about this horrible, inexorable condition. Everyone would like to see an effective new Alzheimer’s therapy!
An answer to these worries, naturally enough, would be to point at the efficacy data from the recent lecanemab trial. But as I wrote here, I didn’t find those numbers particularly compelling, and one wonders what the long-term prognosis is after clearing out all that new empty space. But the FDA has tied its hands when it comes to making calls about efficacy in this area by approving aducanumab when the agency’s own statisticians weren’t convinced that its numbers were good enough. Or so it seems to me. So if they’re going to slow or halt the approval of lecanemab, it would presumably have to be on grounds of safety (ARIA and increased ventricular volume). Will they? There’s an advisory committee meeting coming this summer. We shall see. If this doesn’t get discussed, somebody’s trying to cut corners.
It doesn’t feel particularly good to be standing off to the side of all this excitement going “Well, ACtually. . .”, but given these data, I think that’s what has to be done. Sure, we want a new therapy, but who wants one that is actually going to give Alzheimer’s patients even more brain damage? That’s literally what we’re talking about here, and the issue has to be in the spotlight.
