Well, welcome everybody to late breaking readout round table number eight. I'm Steve Salloway from Brown University, and we have an exciting program to share with you today. The title is Dose and Time-Dependent Changes in Plasma p-Tau 181 in patients treated with Aducanumab in the ENGAGE and EMERGE trials. We're very fortunate to have Oskar Hansson and others from outside the U.S. He lowered the immigration standard. He's back in. Thank God and to all of you, welcome back to the U.S. We have Oskar here from Lund University, Gil Rabinovici from UCSF, Jeff Cummings from the University of Nevada, Las Vegas. I think it's gonna be a really great program. None of the participants in the panel have received compensation for participating in this event from the sponsors of this program, Biogen or Eisai. The views that we are expressing are our own. The disclosures, and each panelist can share theirs. My most relevant disclosures are that I was a site investigator for the ENGAGE trial and the PRIME trial, and also the co-chair of the steering committee for the phase III program for Aducanumab, and have received consultation fees from both Biogen and Eisai. I don't think they conflict with any remarks I might make, and I'll let the other panelists comment on their own when they introduce themselves. As I mentioned, Oskar will be presenting these new results, and I think they're exciting about the changes in plasma p-tau with treatment with an anti-amyloid antibody. Oskar's in a great position to do that, having done really much of the seminal work on plasma biomarkers for Alzheimer's. Oskar, please. Thanks a lot, Steve, for that very kind introduction. When it comes to disclosures, I've also been part of a steering committee for ENGAGE and EMERGE. I will present the talk called Dose and time-dependent changes in plasma phospho-tau in patients treated with Aducanumab in ENGAGE and EMERGE. This is just to remind you all that plasma phospho-tau levels are clearly increased in both prodromal Alzheimer's disease and mild AD dementia. There is accumulating evidence that the levels of phospho-tau change very early during the preclinical stages of Alzheimer's disease, just when amyloid PET imaging starts to become abnormal and clearly before tau PET can detect neocortical tau aggregates and well before cortical atrophy. There's a lot of interest, of course, to try to better understand the relationship between insoluble A-beta and insoluble tau tangles. We did just one study in together with Tom Beach, Eric Reiman, and others, looking at data from the pathology cohort where that quantified amount of A-beta pathology in the brain as well as tau tangles. In that study, plasma samples have been collected ante-mortem. We found then that association between A-beta plaques and the number of tau tangles in the brain were, to a very large degree, more than 70% mediated by the levels of soluble phospho-tau. This is just a cross-sectional study, so it doesn't prove any causality whatsoever. Of course, it could be congruent with the idea that A-beta pathology somehow induces increased levels of soluble tau in the brain, which might facilitate the aggregation and potentially also spread of insoluble tau. However, if that is true, we would anticipate that, of course, amyloid aggregates are associated with increased levels of phospho-tau as we know. If we reduce the number of A-beta fibrils in the brain using a drug like Aducanumab, the phospho-tau levels should go down. However, if that change is relevant for the disease, we would also anticipate that the change in phospho-tau levels should be associated with a slower worsening of the disease. The data presented here are from the EMERGE and ENGAGE. To just remind you all that the patients here had either prodromal Alzheimer's disease or mild AD dementia and were followed for up to 18 months. This is just to again remind you that Aducanumab very clearly reduces the amount of A-beta fibrils in the brain, as detected by a serial amyloid PET imaging. As you can see, both in EMERGE and ENGAGE in both the low-dose and high-dose group shown in green and in blue. Two years ago, data were presented on the CSF levels of both phospho-tau and total tau in the small sub cohort that had undergone serial lumbar punctures, so CSF had been collected. The data was very encouraging, showing that Aducanumab reduces the levels of phospho-tau in the low-dose and high-dose group, which was significant then in EMERGE. You also see similar tendencies in ENGAGE. Further, in a small sub-study that had undergone serial tau PET imaging, treatment with Aducanumab was associated with a slower accumulation of tau aggregates as then detected by a tau PET. The objective of this study was now to see the effect of Aducanumab treatment on the plasma levels of phospho-tau 181. The individuals that were selected for this analysis all had plasma samples collected at the 78-week visit and had baseline samples. This meant more than 6,900 samples were analyzed in this study. It was a huge effort. The Quanterix Simoa assay was used to detect phospho-tau 181 levels. As you can see, more than 1,800 individuals from EMERGE and ENGAGE were included in this analysis. These are just the baseline characteristics of the different groups that were included in this analysis, and there is no differences between these groups and overall the population selected here were very similar to the overall EMERGE and ENGAGE studies when it comes to baseline demographics. Here are the results. In the placebo group, there is, as expected, an increase in the levels of phospho-tau with around 8%-9% in both in EMERGE and ENGAGE. However, with the low-dose group, there's a clear reduction in the phospho-tau 181 levels, what was significant in both studies. Further, there was an even more accentuated reduction in the high-dose group. When doing an association analysis, a correlation analysis between the change in amyloid PET from baseline to week 78 in amyloid PET imaging compared to the change in phospho-tau over the same time period, these associations were clearly significant in both studies. We have a correlation coefficient of around 0.4. The more the amyloid PET was reduced, more phospho-tau levels were reduced. This included both the placebo group and the low-dose and the high-dose groups. However, when stratifying the treated groups only, so here the placebo group is not included, but the low-dose and high-dose groups are included. Those individuals that had a normalized amyloid PET scan at the 78-week visit, that is SUVR values in Florbetapir below 1.1, they had a more accentuated decrease in plasma phospho-tau 181 levels compared to those that had SUVR values above 1.1. This was also clear in both studies. I guess this might be the most important slide, at least to me, which I think is very exciting, and I think we can discuss a lot. The greater the reduction in plasma phospho-tau in the treated patients due to the Aducanumab, the slower worsening in cognition. This was then significant for all the four clinical outcomes. This was significant in both EMERGE and ENGAGE studies. Even though the correlation coefficients are not huge, it's still very, I think, clear result from this analysis. To just summarize, when analyzing about 7,000 samples for plasma phospho-tau 181, there was a clear reduction in the phospho-tau levels by treatment with Aducanumab. Further, the greater the reduction in amyloid PET imaging, the greater reduction in plasma phospho-tau levels. There's also a significant association between the change in plasma phospho-tau in the treated group with a slower worsening on all four cognitive outcomes in both trials. With that, I want to thank all co-authors and everyone working here with this study and especially, of course, all the patients and caregivers that have participated in these trials. Thank you. We welcome your questions. Can you hear me? We welcome your questions, so please come up and use the microphone. While we're waiting for people to come up, let me ask the panel a couple of questions. I guess I'll start with Gil. You know, what's your main takeaway from this data, and how do you envision plasma biomarkers like p-tau being used both for screening and as a marker of disease progression and potentially treatment response? Thank you, Steve. I'll just start with my most relevant disclosure, which is that I have consulted for Eisai in the past, unrelated to Aducanumab. I think the data that Oskar just presented are very encouraging and fill a gap in that we had very little data from the original top-line results from EMERGE and ENGAGE about how amyloid reduction impacted tau biology. The number of participants who had CSF studies or tau PET were very small and not randomly selected. I think as we were initially digesting the data, we noted that gap, and we noted that plasma biomarkers might really help us here because the plasma had been stored and could be analyzed post-hoc. I think what we see is very consistent with the results that were presented earlier from TRAILBLAZER, in the sense that we see that reductions in amyloid PETs correlate also and correspond with changes in plasma phospho-tau. I think that this fits very well with the underlying biological conceptual model that we're working with, which is that amyloid in and of itself induces changes in tau phosphorylation and secretion, and therefore reductions in amyloid burden should translate into changes in tau biology. I think that it's very encouraging to see that and also very encouraging to see that the results align very nicely between the two studies, even though the ultimate clinical outcomes have discordant results, positive in EMERGE, negative in ENGAGE. These biomarker results are very consistent, and furthermore, the correlations with cognition in both studies are very consistent, albeit modest. I think these are maybe not unexpected, but confirm not only target engagement, which we already knew from the PET sub study, but now modification of downstream tau biology. We're starting to fill the gaps in terms of how biomarkers might correlate with clinical outcomes by showing the correlations between phospho-tau and changes in cognition. I think we're still missing some boxes here. I think we would very much like to know how changes in soluble levels of phospho-tau might impact fibrillar tau that associates in tangles. I think we'd wanna know about neurodegeneration and how that was impacted either through blood, plasma or imaging biomarkers. We're starting to fill some of these gaps. In terms of how plasma might be used in the future, I think we've seen a lot of data at this conference that suggests that plasma may be very useful as an enrichment strategy, as an initial screen for clinical trial populations. I think these data and the TRAILBLAZER data suggests that someday plasma may be also very useful for looking at target engagement in patients in the clinic and treatment responses. I don't think we're quite there yet. If you noticed, the coefficients of variation of this test was ranging around 8 or 9%, and the overall magnitude of p-tau reduction was 13%-16%. I think that the signal of p-tau reduction is just beyond the noise of the test itself, and that makes me wonder, you know, whether this particular test is yet ready for prime time, something that I can order as a neurologist to monitor potentially in the future a treatment response to anti-amyloid therapy. I think blood biomarkers, both phospho-tau and some of the A-beta data that we also saw from the Lecanemab study, are very encouraging and suggest that blood biomarkers are on their way. Of course, it would greatly make biomarker use much more accessible and cost-effective for treatment monitoring if we were able to at least initially monitor our patients with blood rather than CSF or PET. Maybe, Jeff, I'll ask you this similar question about your initial main takeaway from this data and how you see the field moving forward with plasma biomarkers like this one. Yeah. Thanks, Steve. Thanks for all of our audience for being here. What a terrific observation this is. You know, I think we have wanted to get to a blood test for so long. Now, at CTAD, we've seen 217, we've seen A-beta 42/40, now we see 181. We see that they're behaving consistently, and that they're behaving across different molecules. I think they're giving us increasing confidence that we'll be able to use it to look at the response to treatment. I think the implication is that they will be useful in diagnosis. You know, we still have some work to do there. They might have prognostic importance in terms of higher tau levels predicting faster progression or earlier onset of progression. That would be really useful both for trials and for clinical care. I see the door opening here, Steve, for a wide application of these. I agree completely with Gil that we're not quite there yet. I think methodologically, analytically, statistically, we still need a lot more observations, but these preliminary observations are really encouraging. Can you envision a time where we again make progress, get more data, like you're saying, both of you, where we could use the change in p-tau, plasma p-tau, the lack of change over whatever 12 months or 18, whatever the appropriate time period, as a marker of non-response? As a marker of non-response, no change. Yes, I think that's a conceivable outcome, that we should be able to begin to expect a corresponding response to a successful intervention. If that response does not occur, it would predict an unsuccessful intervention. Okay. Oskar, does targeting amyloid change tau pathology? I guess it comes down a little bit to semantics, what we mean with tau pathology to some degree, but it definitely changes the soluble levels of the phosphorylated tau, which I personally believe is probably very important in the aggregation process of tau. I would tend to say yes, but when it comes to exactly the. I guess they are accumulating data also showing that these therapies have an effect on serial tau PET imaging, at least slowing in the accumulation of tau aggregates. The brain. I think it would be extremely interesting to see if these therapies can really even halt or even reduce. At least what we see now is that there seems to be a slowing of tau aggregation over time, especially in areas that are affected later in the disease, as was shown earlier today. Thank you, Seth. Your question, Anton. Thanks. I want to just throw a question to the panel. Obviously, we've had a lot of controversy about the provisional approval based on amyloid-lowering properties and the connection of amyloid lowering to clinical outcomes. Where are we at for the possibility of provisional approval based on impact on tau? You know, you showed a correlation between tau reduction and clinical outcomes. What else would we need to see for that to become a viable pathway forward at some point, maybe in the near future? It's a very good question, I guess, and it of course depends a little bit on the requirements you want for a surrogate biomarker for predicting a clinical outcome. To really prove it, I guess you would like to target the same molecule through another mechanism and see that if you affect that target with another mechanism, you also have a clinical improvement. For example, if you reduce, let's say, soluble tau levels with an antisense oligonucleotide or something, and if the change in tau associates with positive outcome, I think you would be even more certain that this could be a good surrogate marker. I guess there's accumulating evidence here that it might be. Definitely, we don't have data suggesting the other way around. I agree with Oscar. I think it's still early. I think the data are accumulating. I think many of us in the field would feel more comfortable with tau as a surrogate biomarker for cognitive outcomes because the correlations between the distribution and burden of tau and clinical measures, neurodegeneration are much tighter, of course, than they are with amyloid beta, at least at the symptomatic stage of disease. I wanna say, though, that the magnitude of the correlations was quite modest, right? The correlation coefficients were in the range of 0.15, 0.2. Now that maybe that's not unexpected because we're still when we're talking about soluble forms of phosphorylated tau, we're still many degrees from brain function, synaptic function, the biology that matters in terms of cognition. I don't think it's surprising. I think it's encouraging that we do see the correlations, but we have to remember that we're still measuring something that's quite upstream of cognition and function ultimately in the pathophysiological cascade, at least as we understand it currently. Okay. Anton, of course, always asks them the most challenging questions. I would just say that Accelerated Approval is based on a change that is reasonably likely to predict clinical benefit. That's the actual FDA wording for Accelerated Approval. I think we agree that actually tau has been more likely to predict clinical benefit than and clinical change than A-beta has historically. Certainly we need all of the additional data that we're talking about here. I expect other biomarkers to be predictive and likely to be the basis of Accelerated Approval under appropriate circumstances. Excellent. Question over on the right. My right. This is a great talk regarding phospho-tau 181, p-Tau 217 as a predictive marker. One of the major question in Alzheimer's field we have seen it's a multifactorial disease. It's not A-beta or tau, it's alpha-synuclein TDP-43. Do you guys have you seen any effect on those aggregates in these patients or if they have some alpha-synuclein or TDP-43 aggregates as well in AD? It's a very good question. The problem, I guess, it was still we don't have the methods to evaluate that. There are emerging assays for measuring alpha-synuclein pathology in the sense of seeding aggregation assays. But currently, you need cerebrospinal fluid or you need skin biopsies maybe for that. They are not usually quantitative, just binary, yes, no. It's difficult. TDP, we don't have any at all. In the future, when these markers are around, it would be interesting to study exactly what you say, but we are not there. I think it's a great question, and it also underscores the importance of developing methods to follow clinical trial participants to autopsy. Because ultimately, the way that we'll be able to determine, hopefully we'll have useful in vivo biomarkers for alpha-synuclein TDP-43. Ultimately, what we have now to see how the biology has been affected and will still be valuable regardless of biomarkers, is to study individuals after they pass away and understand how the treatment may have modified the biology of the disease microscopically. I think that's a very important call to the field, and I think it's been said before, but I'll take this opportunity to say it again. We need registries and methods to follow individuals to autopsy. Question on the left side. My left. Hi. Lars Raket, Novo Nordisk. I think this is really encouraging to see and to get this link to patient-level treatment effects that are then linked to cognition. We've really been missing that. I wonder, have you looked even further downstream, to look at biomarkers of neurodegeneration, looked at NfL, for example? Exactly. Yes, it hasn't been presented here, but it will be presented later on. There is such data. I guess there will be also, I don't know if it's ready yet, but I guess also other biomarkers like for GFAP, for example, and so on, will be extremely interested to see. I think that will be analyzed for all these ongoing studies or all these completed studies where plasma samples are available. I fully agree, it's extremely important. Stay tuned for those answers. I wanna pick up. I don't see anybody at the mic at the moment. Steve. Sorry. Ron. Go ahead. Just. Yeah. This is Guoqiao Wang, statistician from Wash U. Although, you know, the correlation from a p-value perspective is very strong, but the magnitude generally is about below 0.2. I'm wondering if the panel can comment on why the correlation in magnitude is small. Also, is there any kind of a subgroup analysis like the progressive, non-progressive analysis, is there any stronger correlation in some of those subgroups? Thank you. Yeah. I think I may have mentioned, but I agree. I think the magnitude is quite modest. When we're thinking about the pathophysiological cascade and where cognition sits and compared to phospho-tau, phospho-tau is very upstream. You know, if we're correct in our conceptual models of disease, phospho-tau may contribute to neurofibrillary tangle spread, which then conversely leads to synaptic changes and changes in brain function, which we then measure with our you know, relatively coarse measures of cognition and function. I don't think it's a big surprise that the correlations are modest. I would say that the correlation between amyloid lowering and phospho-tau lowering was stronger, right? Those correlation coefficients were around 0.4. These are more closely linked in the pathophysiological cascade. I think at least in terms of ranking the magnitude of the correlations, things have gone in the expected direction. A-beta lowering and phospho-tau lowering are more tightly related to each other than phospho-tau lowering is to cognition. I agree that, you know, ideally, we would have biomarkers that would have even stronger correlations with cognitive outcomes. Exactly. I can just add that we can just mention that these data have only been around for a short time, three weeks, something like that. The subgroup analyses are on its way, and we'll present it at future conferences. Yeah. I just wanted to echo this question about subgroups, because I think looking at the severity of the amyloid deposition at baseline and the magnitude of change at baseline of the p-Tau 181 also very important to determine really what we're seeing and what is the relationship of the baseline of the patient when we look at these changes. No other questions that. Oh, yes. One of the burning questions that's consumed the field is why high dose Aducanumab in ENGAGE didn't show any signal at all, actually slight decrease. I assume that in the analysis so far of p-tau 181 decline, there's no hint at the high dose ENGAGE behaving any differently than the high dose EMERGE. Is that right? Or did I miss that? No, no. You're right. In both studies, where the great reduction in plasma phospho-tau, the slower the worsening of disease, and that was clear in both studies. When there is an effect on phospho-tau levels, there seem to be associated with a slower progression in both studies. In point of fact, high dose ENGAGE didn't achieve its endpoints and was neutral basically in terms of not showing a change in the clinical study. Exactly. That is not explained by these findings, I would say. No. Right. I think it's important, maybe Oskar, you could explain how the participants were selected for this analysis, because I do think it's very important to understand that these were all completers. Yeah. If you could explain just a little bit. Yeah. Exactly. As mentioned, the ones that we included were everyone that had plasma samples at 78 weeks and baseline. Those were the individuals. Everyone that had completed the studies. It's not a full studies either. Yeah. That could explain the difference. One of the other observations that's interesting in the CSF data from the two studies is that 42 levels rose with treatment in EMERGE. Even though it was a small number of CSFs, I think all of those subjects who got LPs in EMERGE showed 42 levels that went up, and the 40 level didn't really change during the 78-week trial. In ENGAGE, that wasn't the case. There were about half the CSFs that were sampled showed a return of 42 to the normal range and the other didn't. One wondered again whether that was associated with a very slight difference but rather meaningful difference in A-beta lowering across the full trials of ENGAGE versus EMERGE. There was maybe 12 or 13% less amyloid lowering by PET in ENGAGE and EMERGE. It's interesting that there are some differences in biomarkers, but it's an important point that in this dataset, which are completers, there's no difference in the effect in ENGAGE versus EMERGE. Correct. Right. I think we're at the end of our time. I just wanna echo a comment that Jeff made about where I think we're at the beginning. This is my bias, not related to any company. We're at the beginning of a new treatment era for Alzheimer's. For a long time, we've wanted drugs that could lower amyloid. We wanted to be able to measure it, first with PET and now with a series of and looking in plasma at A-beta and in phospho-tau. They're moving in the right direction, and they're giving us, you know, a opportunity to really build on this. I think the key is to figure out the next. We're out of time today, but the key is to figure out the next steps so we can, you know, continue to move the field forward. I think we're in a much different position than we were 10 or 20 years ago when we were planning and hoping for this to be at this moment. I wanna thank the panel, thank Oskar for presenting, and thank the panel for excellent comments.