How long are we going to keep doing this?
I ask because Roche announced results from a trial (API-ADAD)of their anti-amyloid antibody crenezumab in a population that’s genetically susceptible to Alzheimer’s disease. It failed. Just like it failed the Phase III CREAD trials in a general aging population group in 2019. This trial was in an extended family network in Colombia, who all have a mutation (E280A) in their presenilin gene that disposes them to amyloid-driven neurodegeneration starting in their 40s. No benefit. Just like an earlier trial from Washington University in other patients with mutations that dispose towards disease, that one looking at an earlier Roche anti-amyloid antibody (gantenerumab) or Eli Lilly’s solanezumab. That’s after solanezumab itself had failed painfully, expensively, lengthily several times in its own clinical trials against Alzheimer’s. They have another antibody (donanemab) in trials, but I don’t think that one’s working, either (Lilly has made it some sort of principle to keep trying the amyloid hypothesis over and over again). And all of this is after bapineuzumab, a pioneering clinical candidate in this field, failed several years before. If you would like to see a recent list of all these failed clinical trials, this review will summarize them for you – out of sheer frustration, I’ve left some of them out of this post, if you can believe it.
It is hard to even begin to estimate the amount of time, effort, and money that has been spent on this idea. And this is just the antibodies! There are plenty of other whacks that have been taken at the amyloid hypothesis (secretase enzymes and more), and none of them have ever worked. Keep in mind that there are plenty of preclinical efforts over the past thirty years that never even saw the light of day (I was on some of those myself), and the reason you never heard about any of them is because they didn’t work, either. Nothing has worked. Not once. The amyloid hypothesis has been targeted again and again and again from different directions with different drug candidates, and never, ever even once has it shown signs of truly helping Alzheimer’s patients. I very much include Biogen’s Aduhelm in that assessment. So I ask again: how long are we going to keep doing this?
Over the years I’ve chronicled these failures, with greater and greater amounts of disbelief and frustration creeping in as I watch the pile of wreckage accumulate. Always there’s another trial, another agent, another approach coming, and that’s where the hope resides, perpetually. We just haven’t done amyloid the right way. We haven’t dosed early enough, in the right patients, in the right way, targeting the right sort of amyloid. The fault is not the amyloid hypothesis, friends, it is in ourselves. Somehow our offerings have not been deemed worthy, and we must sacrifice even greater numbers of captive warriors on the Temple of the Sun God. . .whoops, I mean run even more clinical trials in order to see its true glory revealed.
And that’s what we’re doing. There’s another readout for gantenerumab coming later this year. Donanemab is still out there. Biogen and Eisai have another one (lecanemab) in trials. There are still people saying that one of these is the real test, the fair test for the amyloid hypothesis – but my belief is that they are extremely likely, overwhelmingly likely to fail, and if they do, there will still be people saying that things are progressing, that these failures are pointing the way to success, that we’ve really got the amyloid hypothesis right where we want it now and we’re closing in. I’m not buying it. I am done, and I have been done for several years now. I do not believe that targeting amyloid is going to lead to a useful Alzheimer’s therapy, and watching these trials feels to me like watching someone trying to put out an oil well fire by dumping duffel bags of money onto it from helicopters. Hell, that would probably be cheaper. I don’t know what the answer to Alzheimer’s is, but at this point, as far as I’m concerned, it isn’t amyloid.
