[We will] be discussing the amyloid beta targeting therapies in Alzheimer's disease session two. I'm Randy Bateman. I'm a professor of neurology at Washington University and the director of the Dominantly Inherited Alzheimer Network and Trials Unit. Chad? Hi, everybody. I'm Chad Swanson, in the neurology business group at Eisai in clinical development, and I am the international project team leader for lecanemab or BAN2401. Great. Mark? I'm Mark Mintun, and I head the Alzheimer's disease development area for Eli Lilly and Company. Great. Samantha? Hi there. Good morning. Good afternoon. I'm Samantha Budd. I work at Biogen, and I head up the Neurodegeneration Development Group. Thank you. Okay, Austin. Hi, I'm Austin McCullough. I'm a graduate student in Tammie Benzinger's lab at Washington University in St. Louis. I primarily work with neuroimaging data, dealing with the DIAN and DIAN-TU. Great. All right. Everybody has given a presentation in this session on drugs that target amyloid beta removal out of the brain. Some very exciting data is coming out and has come out related to these drugs and their impacts on the disease state. We have a lot to talk about and questions to answer. If the audience would like to send questions to us, you can do so through your session. We'll see those, and we will ask the questions of the speakers. We'll try to keep our responses to around one minute or less so that we can handle a number of questions. Randy, I would ask for folks sending in questions to indicate the presenter that they'd like to address that question, if possible. That's a great idea. Yeah. Please indicate who you want to answer the question, and then that will help us direct the questions to the appropriate person. I'll start with the first question, and this will be for the group to address, and so people can volunteer to answer it. Given the findings that we've seen so far in drugs and antibodies that remove amyloid plaques out of the brain on the amyloid imaging, on some of the phospho-tau measures, tau PET, and the cognitive and clinical findings that are coming out of phase II and phase III trials, what commonalities do you all see across the studies, across the programs in terms of what does this mean for the disease, the disease progression? What does it mean for the biology of the disease, and what does it mean for the therapeutic opportunities? I'll open that up for anyone to take that one. I'll jump in there and say that obviously it's been really exciting, I think, for the field to see that the amyloid cascade hypothesis gets more and more data, it seems every year, more and more support. I think the commonality here is that we're attacking amyloid. We're making measurements that demonstrate that we're successfully removing amyloid, and we're seeing signals that indicate we're slowing the disease. I think that's fundamentally the commonality. I think there are differences. Each drug has slight differences and some people can sort of look at different ways that we're attacking the amyloid beta. Those will have to be, I think, taken seriously, and I think the field has to sort of track that down. Fundamentally, this is an aggregate, I think, great support for the amyloid cascade hypothesis. Yeah, I can agree with Mark very much so that here we have, and we're talking about three molecules, Chad, Mark, and myself here today, and the commonalities are striking. You've got three molecules that robustly lower amyloid plaque. They've each shown associated reductions in clinical decline, and they've also each shown an impact, either using CSF or imaging, a reduction in the downstream tau pathophysiology. I think that these are really exciting findings, and especially as Mark says, on the backdrop of they're three different molecules. There are slight differences among them. The clinical trial designs are also quite different as well. So being able to withstand that backdrop, having these reproduced effects across different molecules is really the strength. Yes. Certainly agree. Clearly very similar findings across efficacy in terms of clinical measures, even downstream biomarkers, for instance. I think one of the interesting things about this is that these studies all, as usual, start at slightly different times, and there's generally different things available at those specific times. I think this particular biomarker field evolves so rapidly that it's difficult to get exact comparisons along those lines. I think as we progress and we see more of these kinds of studies in molecules, I think we'll gain an even better understanding and probably hone in a little bit more on what these commonalities are and what they mean. I would just add that I'd also like to see, with respect to amyloid specifically, what's happening with other kinds of amyloid species, for instance. We talk about amyloid PET a lot, of course. It would be very interesting to know what's happening to, say, the soluble aggregate species in some of these studies. I think that's maybe a forward-looking thing for the future. Great. Okay. Chad, did you want to ask the next question? The next general question? Sure, yes. Quite a few have been coming in here actually. I have to go to the beginning. This is a question for Mark. What was the rationale behind reducing doses or switching patients to the placebo arm based on amyloid PET scans during the trial? Could this design impact the results of the trial, both primary and secondary endpoints? Yeah, no, it's a great question. No, it's an important one because, in some ways, it looks like we deviated from the norm here. If you come at this as sort of treating a target, you're treating, in this case, the amyloid plaques, specifically with the N3pG modification, N3pG modification. Our sense was that we treat the target. In other words, when the target is no longer there, we stop treatment. On one hand, that sounds odd because other trials have started and will continue treatment and without any obvious endpoint. Our sense was is that we were getting such dramatic reduction of amyloid in our phase I trial. We could actually aspire to being able to take people off drug. In a way, it's not that different than radiation therapy for a tumor in the chest, and you radiate it and radiate it and radiate it, and you image it and it's not there anymore, and someone biopsies and says they can't find it. You don't continue treating the target anymore because the target's gone. It's not a perfect analogy, but our sense was is that we wanted to incorporate that in the trial because ultimately, if we can remove the amyloid, other evidence by pretty much everyone on this call have shown that amyloid removed by these methods doesn't come back. We had shown that also to an extent in our own phase I. Our sense was is that the target is not coming back in a period of years, then we wouldn't have to continue treating. We did that. Obviously, one of the questions that is implied in that is, well, gosh, if you took people off drug, maybe they started getting worse again. We actually were able, at the end of the trial, to look, of course, because people could go down to placebo right away, they could go to placebo late. We were able to sort of histogram all the total doses received by the patients over the whole trial. Basically, the people who received in the lower half of doses had exactly the same differentiation from placebo as the people who was in the higher amount of doses. Whether you dropped really fast and then went off drug, or you dropped continuously and ended up staying on drug a longer period of time, it didn't seem to matter to the efficacy against placebo. Okay, great. Thanks, Mark. There is a flood of questions coming in, some of them, well, most of them are quite specific. I'm going to try to group several of these questions together into a more general question. This one, I think I'm going to field to Chad, if you'll take this. One of them is the effective time off drug. Mark was just talking about duration on drug and when to stop the drug for treatment. In your open-label extension, you had the opportunity to look at treating for a certain time, stopping, having people off drug for a period, and then restarting the drug. Some of the specific questions that are coming up is: What is the effect of that? If someone stops drug, does it tell us something about the state of amyloid when they stopped? Is there a differential effect when they restart, depending on how long they've been off for? Is there a clinical implication to this of how long someone can be off of an amyloid-removing drug before restarting? Right. Yeah, that's an excellent series of questions. Thanks. You'll recall from the presentation that both mean and median time off drug was about two years. While there were some pretty big extremes, right, nine to 55 months or so, most of the subjects sort of congregated around that two-year period. I would say that the ability to remove amyloid is most likely related to sort of the starting level, the PET SUVR, for instance, for these subjects when they start. For instance, at the open-label extension, those who are more kind of like, in words used from my presentation, core-like, so starting this study, right, if they're at sort of levels of 1.4 roughly, 1.36, something like that. There's a greater opportunity to remove more amyloid, versus a subject who might have been treated with the top dose ten bi-weekly, which already had pretty robust reduction in the core period. We see that they do continue to see reductions in their amyloid, but it almost approaches a floor. I'm a little reluctant to say that's a definitive statement, but it does appear that there is kind of a commonality that they're all approaching at that point. I think that's probably the most important feature of amyloid removal. Okay, great. I can extend that to Samantha, Mark, and Austin. Any further comments on that or thoughts about that in terms of amyloid removal, time off or time on? Well, I think as Chad was saying, and Mark said similarly, once it has occurred, appears to be quite stable. Chad's appropriately cautious about what is the bottom of removal. Wonderful. Sensitivity of the tool, right? I think what we don't know yet enough about is the clinical consequence, because plaque reduction is one of the elements. Chad also was discussing earlier, we know there are soluble oligomeric species that also play a role in the disease. In your studies, Chad, in that gap period, patients did continue to progress in disease. By removing the amyloid to a fairly low level, you didn't stop the disease completely and utterly, right? This removing the tumor analogy, as Mark's saying, isn't quite accurate yet. I think we've a lot to learn about how long and how low do we need to go in the plaque. Do we also need to keep in check the other oligomeric species, and how do these relate to somebody's progression in the disease? Of course, we have the backdrop of stage of disease at which treatment was initiated. I was very excited to see the work from Mark's presentation this morning, looking at the tertiles on the basis of tau. Really showing us who is able to respond to an anti-amyloid treatment. I think what we learned from that information is that there may be patients who are too late for an anti-amyloid treatment as well. I think there's a lot that we have yet to learn about these things. Yeah. Thank you, Samantha. I would just like to add there, that 10 mg per kg dose in the core, those subjects were roughly 90% of them are amyloid negative. As Samantha aptly points out, they did continue to progress, albeit they progressed at the same rate it looks like as placebo. There's something to be learned there, but I think it does suggest a role maybe for other amyloid species or other targets as well. I think soluble amyloid species might be playing a role there. Yeah. Thank you. One of the things that's difficult about this is, of course, in this post-trial sort of evaluation, and we'll be facing the same thing in our extension trial. The numbers get a lot smaller, and one of the interesting aspects is what Samantha referred to in my talk, which is the levels of tau underneath what may be very similar clinical phenotypes can actually cause a lot of heterogeneity. We've known that it's hard to do any Alzheimer's clinical research with small numbers of patients. It looks like that would be one of the major sources of the underlying complexity of this. As we think about doing things, we'll, I think, have to keep an eye on how we can stratify any sort of small numbers of subjects into, for instance, a tau pathology extension. I think that makes it really complicated to evaluate the small amounts of data that we often get in this type of situation. I'm seeing a series of questions in response to the discussion, and they really track on two areas. One is targeting amyloid and its how long, and how low, and when to start, and when to stop, and who to treat. The other series of questions are focusing on other targets. They're not amyloid plaques necessarily, but they're focusing on oligomers and tau and what effects that has. I thought I would kind of frame a general question for both and have each of you discuss this. One is, given the data so far and the clinical trials that have come out for amyloid-removing drugs. The question of how long to treat for, and how low to go, and when to start and stop, we've addressed that. One thing we haven't touched on yet, though, is we haven't touched on who to start with. I'll direct this one to start with Austin, because Austin, you presented data from the DIAN-TU trial on two very different groups of people who had amyloid. A pre-symptomatic group that had relatively low amounts of amyloid and a symptomatic group that had much higher, SUVRs above two for symptomatic amyloid. You emphasized some of the differences you saw. For example, you mentioned the pre-symptomatic group got below an amyloid cutoff, the symptomatic group did not. That you also mentioned that mutation carriers are producing more amyloid than sporadic. Would you comment on, in terms of populations, pre-symptomatic versus symptomatic, and you can comment on the DIAN-TU trial as well as sporadic AD. What difference do you think it makes in terms of removing amyloid going before symptom onset versus after symptom onset? Right. I'll expand the rest of the questions for the others. Yeah, I think what you can see in the data that we showed is that there is a definite value to starting treatment on a patient when they're early in their accumulation vector of amyloid, which is how I like to look at it. Every patient has an accumulation vector that might be higher or lower. In those patients that are pre-symptomatic and have lower levels of amyloid, you can see a much quicker turnaround in their vector, essentially. We can get it to where they're reducing their amyloid load levels. We can get them down to where they're actually getting to a point where they're below what we would consider as negative threshold on PiB PET. That's despite the fact that they have a dominantly inherited mutation, which is quite impressive. The individuals who would qualify as CDR greater than zero, already displaying cognitive symptoms, although we get that same level of reduction. Their disease vector is so much higher in terms of how quickly they're moving in that direction. You can lower their amyloid levels, but it only does so much, right? You may need to have them on the treatment for much longer to get them to that same level where we would consider them as amyloid negative. Okay. For sure. We're working on analyses right now combining the data from the DIAN-TU with the Marguerite RoAD and Scarlett RoAD trials to sort of try and get at that idea of there's a definite value to how quickly the person is accumulating when you start the trial. Stage of disease for amyloid growth may be important. Mark, you touched on and communicated well in your presentation the difference between tau pathology stage of disease by tau PET, and that that may be an important factor in terms of response. Some questions that I've received is, this is directed, I guess, to Samantha, could some of the difference between ENGAGE and EMERGE, could some of that difference be due to this stage of disease issue that maybe there was people with more tau PET in one of the phase III studies than the other that could account for some of the differential observations? That's an interesting question. We did not have tau PET at baseline for all of the individuals. We did include tau PET in both studies as a subgroup towards the end of the two studies. It's a really very small subset. Whether that would've contributed to the difference between the two studies, as I say, formally is unknown since we didn't measure it, but on the basis of other disease characteristics, so their baseline clinical scores, and other demographics and even amyloid, they were very well-balanced across the two studies. We don't believe that baseline heterogeneity of disease is really the difference between the two studies. We do think that dosing has played an important role in the difference between the two studies. It's a very interesting question, and I think we have a lot to learn around the role of tau, and the data this morning is really advancing us on that. I would say that what we know from pathology is if the population in EMERGE and ENGAGE is likely to be as high as 90% positive for tau. The presence of tau is very probable in the population as defined, since they are already symptomatic. Great. All right. Chad, did you have a question or a response? Sure. Yeah. No, I maybe could go into a question here. Maybe this is switching gears just a little bit, and this is probably, well, it is directed towards Mark, but I think it's maybe a more general question, and that is, could you please comment on the utility of iADRS versus CDR Sum of Boxes as primary endpoints in the early symptomatic population, and would one be more appropriate than the other? I think it's a very interesting question given the results that you've shown and I think others have shown recently. Yeah. There's a bunch of questions in there, we're talking about tau and about the exact species of amyloid that we should be going after because there is that one interesting aspect that donanemab is pretty selective for, well, very selective for the N3pG epitope that doesn't occur in soluble amyloid. If you were sort of thinking, in a relative way, "Well, what's playing the bigger role?" The efficacy we're seeing in our TRAILBLAZER-ALZ study does sort of indicate that you can achieve that efficacy with essentially not attacking directly any of the oligomers. It's an interesting footnote that we should put there. The other thing I think we were talking about was the issue of the distribution of tau, and I think you're right, Samantha, that in an amyloid-positive population, there's probably only about 10% or 15%, maybe, that is in the lower zero, very low or zero tau. It is, of course, more variable on the other end. One of the interesting things is that our population, although did not have the high tau, we didn't exclude that. That also, oddly enough, made it actually a little higher age, a couple of years older, and a little broader MMSE range we could include because we were screening for the tau level rather than the phenotype level. Interesting aspects there. Chad, I'm going to apologize. I was just thinking of the other questions. Could you repeat that question? Sure. Sorry about that. It was essentially commenting on the utility of iADRS versus CDR Sum of Boxes. Yeah. Obviously, the iADRS has validation data, has already been in phase III studies as a secondary, is composed of the ADAS-Cog 13 and the IADL. As a composite, it has lots of face validity, because it's using these well-known and validated. It's a composite of two, a functional and a cognition. We did it, of course, because it has the face validity of having both cognition and function in there, which we think is very important in tracking disease course. Its statistical properties are so attractive for smaller studies and being able to get a signal out of a smaller study. When you're trying to do a proof of concept study, you can do that in a more dramatic way with a more robust measure. It is absolutely true that there is also a fair amount of acceptance of the CDR Sum of Boxes. We see them both playing an important role in the field. I do note that in our own EXPEDITION 1 and 2 studies, we have had seen variability in the outcome. Two sister trials, exactly the same recruitment, same population. The CDR Sum of Boxes did not replicate between those two phase III trials while the iADRS did. Clearly, one of the data sets that we used to get more comfortable was our own multiple phase III trials over the, so one, two, three, four, five phase III trials. We had a fair amount of data there. Let me just note the timing. We have five minutes left. We have about 70 unanswered questions. Although you all have touched on it. That's only because we had 200 questions come across. You all have answered a lot of the questions in your responses that have come up, questions about oligomers and other things. I'd like to organize the responses now maybe into a lightning round response of two topics. One will be centered on the generalizability. In the clinical trials that have been run, how are those generalizable to the population? What does it mean? The second is a series of questions we received about what does the future hold. Are you optimistic for the amyloid removal as a treatment option? What does it mean for the future of clinical trials and treatments in patients? Things like combination and other targets or other approaches are mentioned in some of the questions. If we each took 30 seconds to address generalizability, so you have to have a very succinct but meaningful answer about this, then we could talk about what the future holds and still make it in time. It's going to be tight. For the generalizability, the questions have centered on cognitive and clinical ranges of people who are enrolled in the trials. We've talked a bit about the tau PET staging and amyloid staging of people. A specific question centered around APOE4 prevalence versus the general population of Alzheimer's disease. For the treatment trials that are done, what are the implications or what do you think are the important factors in this generalizability question? We'll just let anybody start. I'll jump in, Randy. For generalizability, one thing we have in common is all of us are testing patients who have been tested as positive for the presence of amyloid pathology, and I do think that that will be important. Our mechanism of action, of course, is removal of amyloid. We need to have the target present for efficacy. For aducanumab, we have had patients from an MMSE of 20 through to 30 in the clinical trials, and we haven't yet seen a point at which there is less efficacy. We don't know yet, can we go later? We believe, given the hypothesis, that going earlier would be important also to explore. I think, again, another area that there's a lot to learn, but this is quite a broad population already that we have an understanding of. Yeah. Maybe I'll go next. I think, again, we've discussed the commonalities, and I think the fact that we are seeing pretty consistent effects clinically and on other markers. Again, Samantha makes mention of amyloid, and that's the one thing that we know all of these subjects have to have in common. I think one of the potential hurdles, of course, has been the fact that amyloid PET imaging is not so easy sometimes. Now, Randy, with your talk earlier this morning, I think the accessibility kind of comes in perhaps as we start to explore other ways to look at that amyloid positivity like plasma biomarkers and things along those lines. I think it does offer sort of an expansion and more reach to subjects and Alzheimer's to patients. Thanks, Joe. Yeah. My quick answer is that I agree with what's just been said. Obviously, the data we have on the tau and perhaps the limited efficacy of high tau, we have to get to the bottom of that. I think as a field, we have to understand that a little better. It does have some face value that a widespread tauopathy going on in the brain might not be slowed down by removing amyloid at that point. On the other end is accessibility is also has to do with getting people diagnosed. I think, Randy, you touched on this already today, which is the huge value of being able to have blood tests that identify people at high risk for having the pathology, for instance, amyloid, in question. I think blood tests are a key part of therapies and blood tests to be able to find the patients that are most suited. If we need to do precision medicine type approach, then we probably have to do it. We may not. The data, I think, may tell, but we have to be worried about that. First, let's make sure we can find the patients. I think a combination of blood tests and more widespread imaging on the people who are high risk would be the right way to go. Okay. We're really at time. I think we're in our last minute. I'm going to ask, maybe I'll summarize and make a statement. That's the easy question. You left the easy question to the end. Right. Why don't we do our own facial or thumbs up emoticons. How do we feel about removing amyloid plaques as a treatment for Alzheimer's disease? Do we think that either in its current form or some future form, that this is likely to be a treatment that will be valued and helpful for patients and family members? Given that we are in the last minute, let's do some thumbs up. You can do one thumb up, two, or both down. All right. Well, this group is decidedly two thumbs up for removing amyloid plaques. We think that the future is bright, that that's a good thing to do. I think it's also fair to say, though, that how that's done and when that's done and who that's done in is critically important. I'm sorry, Randy. There's a thing in the chat that just says we actually have five more minutes. They gave us five more minutes. Yeah. That's fantastic. We're on fire, guys. They're extending our time. All right, great. We can do more than thumbs up and thumbs down, and we can address some of these other questions that are coming in still. Although I am supposed to be in another session right now, so I'll have to bow out in five minutes. I'll have to excuse myself. Okay, thank you for that. Let's expand on that a bit, because there was quite a few questions about this. What does it mean to remove amyloid plaques in a patient who's already symptomatic? There's been a range of numbers out there, and I'll throw out just in general, 20% changes in some of the cognitive clinical measures, 30% slowing in others, depending on how you measure it, the study, the design, things like that. One of the things that clinicians and treating physicians want to know, and families and patients want to know, when they sit in the office and you're talking about a decision of, we have this drug, it can remove amyloid plaques out of your brain. There's some risk to it. There's the chance of ARIA, A-R-I-A, you explain what that is. There's some clinical risk potentially for other things, and it requires infusions or injections every two weeks, every four weeks, something like this, where now I'm painting the picture of a doctor's office and patients and family members sitting there listening to this. When we talk about what the drugs do and in terms of our optimism or our enthusiasm, how would you all interpret this? Based on the trials that we have, and I'll paint some obvious ranges that I don't think anyone will take the extreme. There's these drugs out there that remove these amyloid plaques, but it really does so little, it's really not worth the bother or the cost or whatever, and I really recommend we do some other management and treatment things. Maybe at the other end of the spectrum is we have this fantastic drug that'll remove the pathology of Alzheimer's disease from you, and this is going to just help the disease tremendously, and we have to start on this life-saving drug right away. Two very different perspectives based on the data. My guess is each of you will land somewhere in between, but how would you describe this to a physician or a patient or a family member? Randy, you painted something which is very interesting in that these conversations are really between patient, their family, and their physician, and their interpretation of the meaningfulness of the data. You talk about these patients as symptomatic, but actually, all of our clinical trials that we have been discussing here are in patients at much earlier stages of disease than previously. They have a lot of life yet to live. They are still, some of them working, they are still productive socially. They are members of families. There's no treatment today at all available to them to stop or slow what they're experiencing. Some of them have families with Alzheimer's, and they know where this is headed. What we're looking at here in some of the results that we have, we have upwards of 40% effect on activities of daily living, meaning that almost 50% slowing of disease. In a two-year timeframe, a year would be normal. We're starting to get to those kinds of numbers. Referring to just one of the endpoints, 20% at the lower end, we need also to look at across all of the clinical scales that are being measured, measuring things that are important to patients, the ability to continue to drive, to continue to go to the store. These are priceless. We understand this is always a very personal decision. Samantha, is that something you think the data supports that the drugs will allow people to continue to drive and go to the store? Potentially, yes, for patients who initiate treatment early enough, who still have those capabilities. These are treatments who their mechanism is fundamentally to change the course of disease, to slow down progression to those milestones of loss of functions. Okay. Chad, what's your take? Yeah, no, I think Samantha makes excellent points and of course, these activities of daily living are very meaningful. I might even bring it back to those 20%-30% changes in other measures. I think she also made the point that this is still a very early stage of Alzheimer's disease and change, particularly in an 18-24-month study, isn't so great. Right? In terms of progression, I'm talking. These 20%-30% changes are probably, again, this is a bit of speculation at this point, but if these drugs are disease modifiers, that change should only grow over time or at least maintain over time. I think that's a really important thing to consider, when we think about the magnitude of change that we're seeing. It's an early population. Yeah. I think it is meaningful and in the numbers that I displayed today, if you look at the graphs, it's basically like stopping the clock for six months. It's on both the iADRS, CDR Sum of Boxes, the IADLs. The treated group at 18 months is basically doing as well as the 12 months into the placebo. In some ways, it's not necessarily as easy to talk about this in terms of 0.39 CDR Sum of Boxes units. If you can talk about it as far as time gain, that might be one thing. The second one is exactly where Chad was going, which is as you think about this as a disease modifier, we start adding up the different pieces of evidence for disease modifier in our trial. The obvious disease modifier evidence could potentially be the amyloid. I think we understand that that's very strong evidence that we've changed the pathology. Another piece of evidence is the issue of the tau. We had tau imaging in all of the subjects at the end, and the regional slowing of tau into the frontal lobe in particular, 60% slowing. For this population, that might have been the next big area that tau was going to spread into at their stage of the disease. Seeing that 60% slowing seen in our numbers should actually mean, given all what we know about the way tau predicts future decline, means that we're hopefully setting those patients up for declining even less in the future. Okay. Fantastic. I think that puts us right at time, and it was an exciting session. I want to thank each of the panelists, and for joining and for all the fantastic questions that we received. Thanks, everybody. Thanks, everyone. Thank you, Randy. Bye-bye.