Amyloid-Targeted Strategies in Alzheimer Disease Management

Jeffrey L. Cummings, MD, ScD: Marwan, maybe I’ll ask you to pick up on that series of thought. There are 2 monoclonal antibodies [mAbs] in phase 3 studies in early Alzheimer disease. They’re BAN2401 and gantenerumab. Could you tell us a little bit about how these molecules are being used to approach mild Alzheimer disease? What’s been seen? What do you expect to come out of this?

Marwan Sabbagh, MD: It’s a very broad topic. We could spend a whole hour just talking about that. BAN2401 and gantenerumab are the latest in many monoclonal antibodies: solanezumab, crenezumab, bapineuzumab, etcetera. We know that each of these different monoclonal antibodies target different forms of amyloid. And the question that people are asking nowadays is, does it make sense to clear amyloid altogether at all—that’s what the monoclonal antibodies do—or is it a specific form of species that you should be targeting? And it is important that these 2 left are targeting specific forms. BAN2401 is targeting the protofibril form. Gantenerumab is targeting a little bit of the oligomeric form, which is a pre-protofibrillary state. So, we will know if it does.

The one thing that’s very exciting about BAN2401 that’s relevant to this audience is that its phase 2 program was very big, and we’re talking about 840 people in a clinical trial, which is usually a phase 3 trial, not a phase 2 trial. I think it was a very informative study. Second is that they found the dose that was appropriate. Third, they showed only for the second time what I call directional concordance, where when you removed amyloid you saw some proportionate clinical stabilization of cognitive decline. That was big because only 1 other drug, aducanumab, has even shown that in earlier studies. So directional concordance has been very informative, that we can remove amyloid and there is some signal of cognitive decline.

BAN2401 is showing a lot of excitement. It has just entered its phase 3 clinical trial. We expect to see readout in a few more years, but the target makes sense. The dose find that led to the trial design made sense. The clinical efficacy signal makes sense. I have to tell you that if you’re ready to throw away monoclonal antibodies, this one still has a strong argument to stay in the game.

Gantenerumab has clear evidence at the higher dose that it can remove amyloid very robustly. They have now gone back into their phase 3 program. We expect a clinical read in the next few years as well. It does have an attraction because it’s a subcutaneous dosing, but the bottom line is that these are the 2 monoclonal antibodies that are left still showing some promise.

Jeffrey L. Cummings, MD, ScD: These are aimed at species of amyloid beta. One of the things that I’ve heard a few people say here at the AAIC [Alzheimer’s Association International Conference] is it’s time to give up amyloid beta.

Richard Isaacson, MD: Yes, they have.

Jeffrey L. Cummings, MD, ScD: Anybody here feel like we have exhausted all of the targets of amyloid beta, or are these 2 programs and others that target forms of the amyloid cascade still worthy of proceeding?

Alireza Atri, MD, PhD: Absolutely. I think we’ve learned a lot about what not to do and what doesn’t work at what stage. But all the drugs, as Marwan said, that have been tested before are a specific population for a specific time for a specific dose for the specific mechanism, and they’re not all the same.

I think at later stages we’re learning that the amount of variance in association between these pathologies in dementia that we can change is probably lower. So, as we go earlier and with different doses, can you still actually have meaningful changes? And I think that ending is still yet to be written. I don’t think we’re there yet. That and there are some other drugs that still affect amyloid. And then ultimately the question is even if you combine it with other types of mechanisms, would you have not just a monotherapy effect but a combination therapy effect? I think we have to do those studies. We have to be thoughtful about how we do it, measure with biomarkers, and probably in those cases do a lot more earlier phase 2 testing.

Jeffrey L. Cummings, MD, ScD: Let me pursue that a little bit with you. One of the other amyloid-related drugs that’s being tested is a BACE [beta secretase] inhibitor. Could you tell us a little bit about BACE inhibitors and why they might be useful in Alzheimer disease?

Alireza Atri, MD, PhD: Sure. The BACE inhibitors are doing a little bit of different strategy than the mAbs. They’re working on the end of decreasing production. There have been several BACE inhibitors tested. What we don’t know really is how much to remove and at what stage. Recently, the development of a couple of these BACE inhibitors have been stopped. In those cases, the levels of suppression or decreased production was very high. So it lowered amyloid levels significantly. The question is whether it was actually too much. There is some evidence that suggests that there’s actually a sweet spot, and the field may have overshot it. The other issue is whether there’s off-target effects for these other drugs, including BACE2 or other things. There is 1 drug right now that is in wide testing, and that’s elenbecestat, and we’ll have the readout of that hopefully in the next year or two, I think.