To what should be absolutely no human being’s surprise, another amyloid-antibody trial has failed. Roche announced today that the Phase III work (two 750-patient trials) on crenezumab after an interim analysis showed a strong chance of futility. They’re still going on with a study in familial early-onset disease in Colombia, and they have yet another amyloid antibody (gantenerumab) in the pipeline, but crenezumab itself for Alzheimer’s in the general population appears to have failed.
You may be wondering about your own memory by this point – it’s hard to keep track, but crenezumab had already failed a few years ago. But Roche kept the faith after subgroup analysis, and went on what is now the traditional route for Alzheimer’s antibodies: move into earlier-stage patients at even higher doses. In fact, that’s exactly the same place that gantenerumab is in, because it too failed an earlier trial only to have development continue. You can imagine what its chances for success are at this point. Not to worry, though – the company’s chairman gave an interview just last weekend saying that he expected breakthroughs in Alzheimer’s treatment in the next few years. To be fair, I don’t think he said that he expected them from his company.
This is even harder on Roche’s partner, AC Immune, who are also working on an amyloid-targeting vaccine. They have programs targeting tau protein as well (such as RG-6100, an antibody that’s also a Roche partnership). Working on tau has the advantage of not having to climb over the huge pile of failures that amyloid-targeting therapies have left, but it might just be the devil that we don’t know so well yet. It’ll be quite interesting to see how the current crop of tau-targeting ideas works out, that’s for sure.
But there are still amyloid diehards out there, and Biogen has found itself leading that list, whether they envisioned themselves in that position or not. As those watching the field know, they have an amyloid antibody late in trials (aducanumab), and another one partnered with Eisai (BAN-2401). The company had its earnings call just the other day, and spent a good part of it fending off questions about these programs, especially since analysts were expecting the Roche analysis to come out very shortly. Biogen, naturally enough, didn’t want to speculate in front of everyone, but I’ll be glad to do so here.
I don’t think that aducanumab is going to work. And I don’t think that BAN-2401 is going to work, either. (Those two links in the last paragraph will take you to longer reasons why I believe that). I would be very happy to be wrong about those predictions, but you’d have to be out of your mind to be optimistic given how anti-amyloid antibodies (and anti-amyloid therapies in general) have gone. I know, I know – earlier patients. Higher doses. Targeting the real form of disease-forming amyloid, the perfect little oligomers/soluble thingies/whatevers that actually like give you Alzheimer’s, instead of what all those crude fist-ax antibodies were doing that came before. I’ve heard all of that. I just don’t believe it. We as an industry have slammed into the amyloid hypothesis over and over, and the results might be trying to tell us something.
Now, I could be wrong about these last anti-amyloid therapies. There is an outside chance that one of them may come through. But “Hey, you never know!” is not a business plan.
As a side point, this field illustrates in fact what I was talking about yesterday on the role of chemistry in drug discovery. In my recent post on a possible infectious disease mechanism for Alzheimer’s, I mentioned Lilly’s gamma-secretase inhibitor in passing as having “done nothing”. A longtime friend in the industry (who knew that program well) wrote to take me to task about that, pointing out that the compound was in fact an excellent gamma-secretase inhibitor and was the best shot at the target ever taken. He’s right, and I’m adding a note to that earlier post. Lilly’s med-chem team and preclinical development group did a great job by getting a compound that good in an area that difficult. But in the end, it was to no avail, because gamma-secretase inhibition does not seem to do anything for Alzheimer’s no matter how good your compound is and no matter how talented and hard-working your medicinal chemists are. So when I say “did nothing”, I mean “for the patients in the trial”, which (sadly) is indeed the bottom line.