Good morning. My name is Jess, and I will be your conference operator today. At this time, I would like to welcome everyone to the Biogen at AAIC 2026 webcast. All lines have been placed on mute to prevent any background noise. After the speakers' remarks, there will be a question-and-answer session. If you would like to ask a question during this time, simply press star one on your telephone keypad. Please limit yourself to one question to allow other participants time for questions. If you require any further follow-up, you may press star one again to rejoin the queue. Today's conference is being recorded. Thank you. I would now like to turn the conference over to Tim Power, Head of Investor Relations. Mr. Power, you may begin your conference. Thanks, Jess, good afternoon, everybody. Thanks for joining us today. I'd like to start by just pointing out that we'll be making forward-looking statements which are based on our expectations. These statements are subject to certain risks and uncertainties, and our actual results may differ materially. I encourage you to consult the risk factors discussed in our SEC filings for additional details. Joining me on today's call are Dr. Priya Singhal, Head of Development, and Dr. Diana Gallagher, Head of Clinical Development for Immune-Mediated Neurodegeneration. You can access the press release and supporting materials regarding today's presentation, as well as a replay of the call at biogen.com. I'll now hand it over to Priya. Good afternoon. It's great to be speaking with you from AAIC. As you know, we also just had good news for patients with the approval of LEQEMBI IQLIK for treatment initiation for early Alzheimer's disease. We at Biogen have chosen to tackle Alzheimer's disease for several years. Having been at the forefront of innovation in Alzheimer's, it is really good to be here at a key Alzheimer's medical meeting with important progress in the field to share. Today, we are pleased to join you to present data for diranersen, which we believe demonstrates an important advancement in targeting tau. The CELIA study was a pioneering effort. What we have observed is that diranersen offers a differentiated approach that leads to tau lowering, demonstrates robust tau tangles reduction in the brain, and importantly, has a substantial impact on multiple clinical endpoints. Several aspects of the CELIA data are unprecedented. As you know, the purpose of the CELIA study was to determine if we could achieve proof of concept, therefore identify a dose to advance into phase III development. We know that many of you have had questions about how we are thinking about this asset because we did not observe a typical dose response with this drug, which was the primary endpoint. What I can tell you today is that we are seeing promising results that importantly provide us with proof of concept and an emerging dose, which is supported by, One, an unprecedented reduction in both tau tangles in the brain and clinical efficacy. Two, diranersen being favored for all doses, showing consistency across the dataset. Three, the 60 mg dose twice a year demonstrating the largest and most substantial benefit across nearly all endpoints. Finally, the results that reinforce the prior findings from the smaller phase I-B study. Furthermore, not only did we see a CDR Sum of Boxes benefit similar to the anti-amyloid therapies at 18 months, but also cognitive efficacy signals not seen before in an Alzheimer's clinical trial for a potential disease-modifying therapy. This is important because while CDR Sum of Boxes is an important endpoint for clinical research, patients and their doctors care deeply about cognitive endpoints and cognition overall. Diranersen now has the potential to be administered just twice a year and has a mechanism that is not associated with ARIA. Let's walk through what we have learned from CELIA with Diana. Thank you, Priya. Let's start with a reminder of the two targets most closely associated with Alzheimer's, amyloid and tau. While the current treatment landscape is focused on amyloid, research has also told us that tau, and more specifically, tau pathology spreading across the brain, is much more temporally linked to cognitive decline. Thus far, as you know, antibody approaches have not been successful in showing clinical benefit. We believe that this may be because they primarily target tau outside the cell and are likely unable to impact the intracellular tau pathology. However, diranersen acts via a very different mechanism. Our ASO targets the reduction of the translation of the MAPT gene into tau protein, thereby reducing the production of all isoforms of tau inside the cell, impacting both intracellular and extracellular mechanisms. Our hypothesis remains that reducing tau production results in overall reduction of tau pathology in the brain, potentially translating to a clinical benefit as a result, neither of which have been seen before in any other tau-directed agents tested thus far. Let's talk about how we tested that hypothesis. On this slide, you'll see our phase II design. Let's remind you of a few key features. This was an 18-month study recruiting patients with early Alzheimer's and mild cognitive impairment, where patients were randomized to placebo and three different dose levels of diranersen. We measured several clinical endpoints, including CDR Sum of Boxes, ADAS-Cog 13, MMSE, ADCS-ADL-MCI, as well as modified iADRS and ADCOMS. We measured total tau in the CSF for all subjects, and then within a sub-study of the population, approximately 30% of the subjects, we also measured tau PET to assess changes of tau across different regions of the brain. The primary endpoint was intended to formally assess a dose response to CDR-SB and change from baseline. Before we look at the results, let's review who we recruited into the study. Here you can see the baseline characteristics of the patients recruited. What you can see is that the arms were generally well-balanced across elements such as MCI versus early AD, as well as APOE4 gene status. Let's talk about what we found in this study. To start, the primary endpoint assessed was whether increasing dose levels improved efficacy compared with a predefined dose-response rate. As you know, we did not meet and observe that dose-response pattern in this trial. Importantly, as shown on this slide, diranersen was favored over placebo across nearly every endpoint though, which is very promising. Let's take a close look at what we saw in the data. Starting with CDR Sum of Boxes, we saw the largest and most substantial effect at the 60 mg every six month dose level. What's most interesting is that for this dose, you're seeing the difference compared to placebo, which is similar to the current anti-amyloid therapy. When we dig deeper into the data for that 60 mg dose, we see a very compelling profile emerge. On this slide, we have placed the 60 mg data from today's AAIC presentation into context alongside results from historical amyloid therapy trials. These are not head-to-head comparisons, we believe they are useful for thinking about our decision to move diranersen forward to phase III. Recognizing the sample size limitations of a phase II, what we are seeing is that the benefit on CDR-SB is similar to anti-amyloid, but with a greater effect size on cognition than what we have seen with other agents. For example, we observe 42% for ADAS-Cog 13 and 50% for MMSE. You'll note that for ADCS-ADL-MCI, we were not seeing separation for the 60 mg dose at this endpoint so far at 18 months. Importantly, we will continue to follow patients and look forward to seeing how this evolves over time, including looking at 24 months. Furthermore, even at the 18-month time point, the story for functional benefit is much broader, as I'll show you on this next slide. That's because when we examine the individual components of the CDR-SB, the benefit is not driven solely by cognition but is also evident in the functional domain. As you may recall, CDR-SB consists of six domains, and the top three on this slide assess cognition, and you can see consistent treatment effect against each of those measures. Interestingly, the bottom three domains assess function, and we also see separation across these as well and a pattern that's reminiscent of what we've seen before on dose response. We believe the fact that we are seeing impact on both cognition and function is encouraging. On the next slide, we'll move into the biomarker data. While we see substantial reductions in CSF tau, as you can see in the top panel of this slide, what further strengthens our confidence in these clinical findings with CELIA is that we're also seeing reductions in tau tangles in the brain as measured by tau PET. Looking at the bottom panel, you can see that in this subset of approximately 30% of patients where tau PET was measured, you see the burden increasing as would be expected for placebo in early AD. However, in all three diranersen arms, tau pathology accumulation was not just slowed but reduced from baseline. This has never been seen before with any other tau-directed agents, and in our view, this is a very important finding. Turning now to safety, what's important to note is that diranersen was well tolerated in the CELIA, with no new safety signals identified as compared to our phase I-B. Most AEs were mild or moderate and not serious, and the majority of patients completed dosing and even rolled into our ongoing long-term extension study. As we saw in the phase I-B, confusional state was reported as an adverse event, and there was a higher incidence of confusional state AEs observed at those higher doses. Importantly, ARIA, which was not anticipated with this mechanism of action, and the results in CELIA were consistent with this expectation. It was not observed. I hope the data we overviewed today helps you understand the CELIA results and the implications. I'm going to now turn it back over to Priya to close out the discussion. Thanks, Diana. I would now like to address what is next for diranersen. First, we will continue the long-term extension study of CELIA to evaluate durability as well as safety and tolerability. We expect to have two-year data for CELIA by the close of 2026. As more of the CELIA data becomes available, we will look to share and publish these data at medical congresses and in the literature. We have also reviewed the CELIA data with several external experts who are equally excited by the results and agree that advancing diranersen to phase III is the appropriate next step. We're now working urgently towards a phase III study design and overall evidence generation package. For both of these, we continue to engage with key leaders in the field and will engage with global regulators as we take a thoughtful approach to determining the ideal design of the phase III and additional data generation approaches. We look forward to sharing more with you in the future. To conclude, we are excited by the opportunity to bring forward diranersen, which we see as having a compelling and differentiated profile, especially with respect to cognition, a tolerable safety profile without increased risk of ARIA, and the potential to be administered just twice a year. I'll note that the dropout rate in the trial was low, and 94% of patients who completed the study have continued into the long-term extension study, which is very encouraging for obvious reasons. Therefore, dosing continues in the LTE, and we have the opportunity to continue to learn more about diranersen, including the two-year data. I hope that the review today helps you appreciate why we are excited about diranersen's overall potential to be the first tau-targeting medicine for early Alzheimer's disease and the reasons that we are advancing it to phase III. Tim, please go ahead and open the call for questions. Thanks, Priya. Jess, can we go to the first question, please? Certainly. Thank you. If you would like to ask a question, please signal by pressing star one on your telephone keypad. Again, that is star one to ask a question. We will move first to Evan Seigerman with BMO Capital Markets. Hi, Priya and team. Thank you so much for taking my question. As we look at the data is it possible that we're knocking down tau too much of the high doses to knock it in effect. How do we know the 60 mg dose is the right dose to take forward? There is a potential benefit of tau in some patients, as you know, and we don't know exactly if you're kind of cutting out too much of that in these patients. Long way of saying, is 60 mg the right dose to be taking forward? Should we be looking at lower doses here? Thank you very much. Thanks, Evan. I'm going to turn that over to Diana. Thanks, Evan, for the question. Yes. One of the reasons we moved from phase I-B, where we had in a small sample size, tested some of these dosing paradigms to a dose-ranging phase II-B, was to answer the exact question you're positing there to determine do we have a path to phase III, and what is the dose? What we see in that 60 mg dose, I think, is that we see the reduction in the tau on CSF as well as the reduction in the tau tangles, which corroborates what we've seen in phase I-B, and we see it across every endpoint that we measured, the key secondary endpoints, with the exception of the ADAS-Cog 13. That's really encouraging to us. In terms of assessing whether or not that we have the dose in its totality right, you see this also, diranersen is favored across every dose. Our goal here was to identify the dose or the emerging dose that we could take forward into phase III, and we think that's what we've done here. Thanks, Diana. Let's go to the next question please, Jess. We'll go next to Salveen Richter with Goldman Sachs. Good morning. Thanks for taking my question. When we look at the 60 mg dose arm, the n was small here. There were a lower amount of patients with APOE4, and there were fewer women in that cohort and lower amyloid PET potentially. I guess what I'm trying to ask is, when you look at all the information you have at hand right now on top of the efficacy metrics, just speak to how you think about further elucidating this on top of the dose work in the phase III trial and the thoughts of doing a combo with amyloid in phase III. If I could just also add, what's driving the confusion state? There's a couple questions there. Maybe we'll take them in order, and I think the first one had to do with understanding what we're seeing in this proof of concept study. It is acknowledged that we were testing three different dosing paradigms versus placebo in that 2:1:2:2. We think we had nice overall distribution in the baseline demographics. Of course, it's never going to be identical. We think that when we're looking at that, we see effect sizes that are pretty comparable across. We've started to look at some sub-group analysis. We will be presenting that in the future. What I can say directionally is that we're not seeing any significant differences based on some of those demographics that you had mentioned earlier. Of course, as we move into a large phase III, we'll be able to confirm that in the next study. I think the next question you had was how are we thinking about designing our phase III? It's a great question, and it's something, of course, we'll be engaging with regulators about in the coming weeks and months. I think first we have to remember this is the first drug that has shown the ability to hit the target, reduce the tau tangles, and show the clinical benefit. We will be engaging with them to understand what is necessary from a sort of dosing standpoint as well as safety and ultimate efficacy in order to meet expectations there. We're really excited about what tau can do for Alzheimer's disease in particular. We also know that we will be hopefully engaging in a market that continues to have utilization of multiple sort of drugs. We're thinking just as you are about future states where patients, based on their personalized biomarkers, may sort of use drugs at the same time or sequentially and more to come there. Right now, we're focusing first and foremost on this tau monotherapy and then thinking about adjunctive data we can generate in parallel to that. I think you had a question, Salveen, about the confusion events. Sure. As we mentioned, you did see that there was an increase in confusion in a dose-responsive way that Cath Mummery had shown on the podium today. I think what's important to note is that most of those events were mild to moderate. Most of them occurred within the first seven days of dosing and then resolved within seven days of dosing, and patients were able to treat through that and continued on diranersen. 94% of patients who were eligible rolled over into long-term extension, which was a question we didn't know from an intrathecal standpoint, how would patients and families react to this? We're seeing a lot of retention for this drug and this route of administration, which we think is encouraging as we move towards phase III. Thanks, Diana. Let's go to the next question, please. We will go next to Eric Schmidt with Cantor. Thanks for the very efficient call. Maybe given this is a bit of a smaller phase II, how did you guys convince yourself that the placebo group is not behaving aberrantly? Any comparisons you might have looked at would be helpful. I know there was also a question about the rate of completion on the study with the higher dose groups having a lower rates of completion. Could you comment? Thank you. Sure. Generally, in looking at placebo, acknowledging this is, as you said, a small study and cross-study comparisons are challenging. We see it's generally consistent with trials, our sort of peer trials, with mild Alzheimer's or MCI. For example, we see the CDR-SB moving at about two points. There are some small changes and differences that you can see when you compare every single trial, but overall, we see it moving as expected. I think you had a second part of your question, which had to do with the higher dose discontinuation. Overall, it is true, and we showed in the disposition on the podium today what those rates were. I think it's important to note overall, in particular, comparability, particularly between the placebo group and the low-dose group. That's something we'll continue to study. Again, the fact that we had high completion rates for an Alzheimer's study, particularly one that's intrathecally administered and high rates of rolling over to the long-term extension, is something that we were looking to assess and are pleased with seeing. I think we're really pleased with the emerging dose and its benefit-risk profile. Absolutely. We're seeing very consistent rates of adverse events and rates of discontinuation. That remains quite promising. Go to the next question, please, Jess. We'll go next to Michael DiFiore with Evercore ISI. Hi, guys. Thanks so much for taking my questions. Number one, what could explain the disconnect between tau lowering and clinical response? You think that the PD effect and clinical response would be positively correlated, but we saw the opposite. Also, why do we see cognitive benefit but no clear functional benefit on ADCS-ADL? Just one more. Why would you say the decrease or benefit on MMSE was so much higher than it was on CDR-SB, especially when CDR-SB is generally considered to be a more sensitive measurement? Thank you. We'll work to take those in order. I think one of the first things I want to do in terms of tau lowering is sort of address that. We definitely understand why you're asking this question. It's important to note that it was a sub-study, so those 131 patients that we were able to have tau, and that there's a lot of individual variability in baseline tau levels, particularly in early AD. We're going to continue to assess all of the different components of that to look at the variation in baseline tau burden as well as other baseline factors and what of all of those could be sort of rolling up into efficacy differences as well as differential tolerability. That's a good question and something we're continuing to examine. Your second question, I think, has to do with ADCS-ADL-MCI. It is a functional endpoint, and it is something that we didn't see moving on that 18-month time point. Interestingly, I'd point you back to the Nature Medicine paper, where when we looked at another functional endpoint, we looked at week 37 and then week 100. We did see there, actually on FA2, that it wasn't moving very much at 37, and then we started to see it at 100. One of the reasons we have a long-term extension is to continue to see if any of these endpoints, which aren't behaving maybe as we would initially expect, change over time. Even separate from whether it does or doesn't move as we look over time, the reason we looked at other composite endpoints was because they have function in them. As you saw on the podium, the CDR-SB has both cognition and function, and we do see a dose response similar to what we saw with the other endpoints on function. We believe we're seeing an effect on function. It's not that there's only cognition. We see cognition and function both in the CDR-SB as well as on the iADRS. That was why this weight of evidence across multiple endpoints, key secondary endpoints, is how we got confident that by targeting tau, we're seeing this clinical benefit. I think your last question was why would there be a disconnect? That's a great question. We're pleased to see the impact on CDR-SB at that level that we are seeing and on cognition and function. You're right. That effect on MMSE, and ADAS-Cog for cognition is really quite remarkable in cross-study comparisons. It's something we're kind of at this pioneering space with what happens when you hit tau, what clinical benefit can you see? We're definitely seeing a significant impact on cognition alongside function. We'll continue to examine over time whether they remain comparable or continue to have this pattern. I want to emphasize that it's in both cognition and function. I'll just add that CDR Sum of Boxes, as Diana mentioned, has got domains for cognition as well as function. We're seeing with ADCS that there could be a lag. We might see this improve at 24 months, and that is something that we're waiting to see the 24-month data. That's going to be an important time point. I think what's really encouraging about MMSE is that it is a test that physicians administer in the office. Seeing such a treatment effect, at the 18-month time point is really encouraging. It could be a function, and I'm speculating here, it could be a function of the fact that tau is really the penultimate sort of protein accumulation before you get symptoms. Maybe there is a differential on cognitive outcomes with an agent that addresses tau. We don't know this. This is speculative, but I would say let's look at the long-term extension data at the 24-month time point and see how these evolve. Thanks, Priya. Can we move to the next question, please? We'll go next to Paul Matteis with Stifel. Hey, thanks so much for taking my questions. I appreciate it. I was wondering if you looked at inflammatory biomarkers or neurofilament at either of the higher doses, and if you see any changes there. I guess just more broadly, it sounds like you don't want to speculate on the mechanism of the inverse dose response. At this point, would you say you're convinced that there isn't some on-target tox when you lower tau too much? Thank you. Yeah. Thanks, Paul. We have looked at inflammatory biomarkers. We haven't yet disclosed that data. We look forward to disclosing it with sort of more data. I would say that it's possible. I think there are several hypotheses as to why a higher dose may not actually translate to clinical efficacy. I think we would be speculating, and I think it's important for us to kind of come back to the fact that we do have a dose that has emerged with a very encouraging benefit risk profile. As you say, tau does have a role in the normal physiology of the brain, microtubules, and neurons. All of this is possible, but I think we are really encouraged and excited by the fact that we've isolated the dose here. Thanks, Priya. Let's go to the next question, please. We will go next to Terence Flynn with Morgan Stanley. Great. Thanks for taking the questions. Maybe two for me. I was just wondering if you can comment at all on the phosphorylated tau data. It looked like that was something you did not present today, but just wondering if that's consistent with what you saw in phase I. On the phase III design, how are you thinking about the primary endpoint? I know when you did the sell-side call several weeks ago, you weren't committing to CDR Sum of Boxes, and now that we've seen some of the other secondary endpoints, looks like the effect size might be more dramatic. Any preliminary thoughts on how you're thinking about primary endpoint for phase III? Thank you. Turning to your first question first on the phosphorylated tau endpoint, we are analyzing that data, and we're looking at it, but haven't disclosed it yet. We have a lot more data that we're going to be disclosing in the coming months, and we can look forward to sharing that. In terms of your question about what will the primary endpoint for the trial be, we will be engaging with regulators, as I mentioned, both in the U.S. and rest of world. I think we have not finalized what that will be. We do see an effect on CDR-SB, which was one of the important things that we wanted to do here. We also see it on iADRS. We also see it on cognition. Again, this weight of evidence we have across multiple endpoints gives us the opportunity to engage in that dialogue. We have an understanding, particularly in the U.S., of typically what their expectations have been. We'll have that conversation with them. Maybe we can offer that we have looked at p-tau181. We know that it's consistent and we haven't shared details, but we look forward to sharing that. Let's go to the next question please, Jess. We'll go next to Michael Yee with UBS. Thank you, guys. Two questions. One is, do you believe that the tau reductions are basically pretty much all the same in overlapping confidence intervals on the doses, maybe all of those doses pretty much give you the same result? When you look at the results there and try to concord that with cognition, that basically all the overlapping confidence intervals are also pretty much the same also on iADRS. To me it looks like only CDR Sum of Boxes is a standout, but all the other ones basically overlap, particularly iADRS. Do you agree with that comment, and would you be open to using iADRS, which is arguably a potentially better endpoint for phase III? I think all things are possible, and we're examining the data, as you said, and thinking about engaging with regulators. Again, we'd like to point out we do see that impact on CDR Sum of Boxes, as well as the iADRS. Seeing it in both places gives us that optionality and flexibility, which we're encouraged by. To sort of toggle back to your question, is it true? It is true, there was a robust impact on the tau biomarkers, both in the lowering in the CSF as well as the impact across the tau PET. We continue to examine that data as well. You're right, we saw very robust sort of target engagement and reduction of tau tangles across all the doses, which was absolutely encouraging. We do think that a lot of those confidence intervals overlapped. We think that it's hard to say that there was a dose response on the tau reduction. The second thing I would just say about iADRS and CDR Sum of Boxes, I just want to be clear that we do believe that the lowest dose has the largest and most substantial effect as of now. We will continue to examine this at the 24-month time point that we've called out. We think it's important, we'll have to see how that evolves. As of now, we believe the low dose is distinguishing itself. That's important, and I think iADRS gives us confidence, right? Because we included a slate literally of all cognitive and composite endpoints that other trials in the anti-amyloid have ever used, and we see a consistent signal. Consistently better at the lowest dose. There may be an overlap in some, but we think that the lowest dose is distinguishing itself. Actually for CDR Sum of Boxes, even the absolute change at the 18-month time point of about 0.54 is quite impressive. We're continuing to see whether that'll evolve. Yeah, we think the lowest dose is declaring itself. Thanks, Priya. Let's go to the next question, please, Jess. We'll go next to Chris Shaw with J.P. Morgan. Hey, this is Taylor Hanley for Chris Shaw at J.P. Morgan. Thanks for taking our question. We were just wondering, can you give some thoughts or color on how you're thinking about the commercial potential for diranersen versus LEQEMBI and Kisunla, just when you're comparing both their efficacy and their safety profiles? Thank you. Sure. It's a great question, and it's one that we've thought about. Just stepping back, we know that about 6.5 million patients have Alzheimer's disease. This number keeps growing. There's an annual incidence of about 500,000 patients. I think the anti-amyloids have really done a valiant job and this market continues to develop. Specifically, as blood-based biomarkers come in, we think that diagnosis rates will increase. The important thing to remember about an anti-tau agent is that we think it offers a different therapeutic modality for patients who have early Alzheimer's disease, and it's actually quite proximal to their development of symptoms. While it's early to really paint a whole treatment landscape, we think that this is quite a large market and there will be different patient segments. As Diana mentioned, who may be typed on a different biomarker profile and would be suited to different options. For example, while the CDR Sum of Boxes at the 18-month timeframe is consistent with the anti-amyloid, we haven't yet seen the two-year data, and we know that the other cognitive endpoints are orders of magnitude different. How will all of this evolve at 24-month time point? What will a phase III show, and how will we design that phase III? Those are questions that we're trying to tackle, but we think there is an important role for a therapeutic modality that tackles tau. I think that we are also looking and very cognizant of the fact that if we are successful in phase III, we would launch into a space that does have anti-amyloid treatment. How do we tackle that? What data do we need to generate to ensure that prescribers are comfortable when they think about all these different patient profiles and a treatment paradigm? I think it's the totality, but we think this is a large opportunity. It's obviously a few years away. We're just at the threshold of starting a phase III, so a lot of work ahead of us, but we believe it's going to be an important and exciting opportunity. Let's go to the next question, please. I'll go next to Mohit Bansal with Wells Fargo. Your line is open. Please go ahead. Hi, this is Sadia Rahman on for Mohit. Thanks for taking the question. Just wondering if you've looked into any subgroup analyses here yet. If that might give you more confidence that any of the small baseline imbalances, for example, on CDR-SB or CDR global scores here might not be driving any differences in these responses between the different doses. Thank you. It's a great question. We showed the sort of overall demographics of the patients and the differential on the different dose groups. It's pretty well bound for a small sample size. You called out a few small changes. I think due to time constraints, we weren't able to show everything in that analysis. Subgroup analysis is ongoing. What I can say is based on what we've been looking at so far, we're seeing efficacy across those patient profiles. We're obviously ultimately going to consider presenting those things, but there's nothing that we're really seeing differentially at this time. I think overall, we're just seeing very consistent overall trends. We've also looked specifically at some very important subgroups like the APOE4 carriers. Yes. We know that there's a differential in terms of can anti-amyloids, are they being used to treat that population? Actually, we see consistent trends across. Small numbers in a small trial, but quite consistent trends. Thanks, Priya. Let's go to the next question, please. We'll go next to Andrew Tsai with Jefferies. Thanks for the update. It's pretty obvious that the low dose is doing the best out of three arms. A bigger picture question could be that, can you guys name some CNS neuro drugs that have succeeded clinically and commercially despite having a lack of dose response? Just wanted to get a sense of how common actually this phenomenon might be in CNS neuro. Thank you. We couldn't understand the question. We heard your first part where you acknowledged that the lowest dose does the best, but we didn't hear the question. Can you repeat it slowly maybe? They might have muted his line. What I think I heard was that, is there precedent in other CNS drugs? Okay. that haven't shown a dose response. I think there are certainly examples where efforts are taken to examine whether or not a pre-specified dose response is met. That hasn't necessarily been seen, but the efficacy shown allows you to move to phase III. Here again, this is the first time anyone's really been able to engage tau in this way. You saw a lot of our doses are kind of close together in terms of target engagement and tangle reduction. What was important for us was to say, do we believe based on the weight of evidence, across all the biomarkers as well as key secondary endpoints, that we have a dose we can move forward? It's really that go forward position, the confidence in identifying that dose. I hope that answers what we got most of your question. I'll just add that we also were taking this assumption from the anti-amyloid, which had really been the only successful drug development program for Alzheimer's disease. There is a fundamental difference. With amyloid, we're looking to clear all of it. With tau, we're not looking to clear all of it. Instead, we're looking to find a sweet spot where we have benefit risk, because tau does have a role in the normal physiology of the brain. There could be fundamental differences in the biology, and that could contribute to the lack of dose response, which was set up as the primary endpoint. Go to the next question please, Jess. We'll go next to David Amsellem with Piper Sandler. Hi, good morning. This is Alex von Riesemann on for David. Thanks for taking our question. We wanted to briefly touch on the Alcyone acquisition you made last year. You've previously said that you were exploring the device for SPINRAZA. We're just wondering if Biogen has an appetite to use the device for diranersen. How do you think this may change its role in the treatment landscape relative to a traditional intrathecal and other IV or subcutaneous options? Thank you. Yeah. It's a great question. That ThecaFlex device, as we said, from Alcyone is something that could be an option that we could build into as we're thinking about designing the phase III, which as Priya said, is still under development. For patients with Alzheimer's, they may, particularly for a twice-yearly administration, want to have different options. For some patients, they might say, going to the doctor and having intrathecal twice a year is fine. Others may say, have complex fine, or they may just say, their families may say, "If I can have the option of an indwelling catheter, that just makes things easier." What's great is that, hopefully we can have the opportunity to offer for patients and families the decision to make on their own. Thanks, Alex. Let's go to the next one, please. We'll move next to Emily Field with Barclays. Hi. Thanks for taking my question. I wanted to follow up, Priya, on one of the answers you just had about targeting that tau sweet spot. Because diranersen lowers tau indiscriminately, with the physiological and pathological. Is that what creates that sort of 60% feeling on lowering tau? Do you think that that's as far as you can go without impacting the physiological tau? Secondly, you flagged baseline tau variability as a possible driver between some of the cognitive outcomes that you showed today. I was just wondering if you're planning on including baseline tau as a stratification factor in the Phase III, or how you plan to explore the impact of that in the future. Thank you. Yeah, maybe I can address the first part, which is, yes. I think that the short answer to that is, no one knows this for sure, and we were testing it in Phase II. What we know from the biology, we were never looking to clear all tau. That was never the goal. I think that we wanted to test the doses and the regimens to see whether we could isolate the right approach, and that is where I was referring to the sweet spot. It is possible that 60 mg twice a year gives us that sweet spot. We're really happy that we have been able to identify that in Phase II, which was really a dose-finding study. Yes, we think there is a sweet spot, and we think that that is exactly what might be emerging here. Regards with baseline tau and how we're thinking about Phase III, I'm going to turn it to Diana. We are thinking about this very deeply. Yeah. I think one of the things that we are obviously going to bring this into a much larger study, and that study will allow us to do additional analyses with much bigger sample sizes where we can look across multiple components. As we said, we can look at baseline tau levels, we can look at also multiple other covariates to sort of further elucidate what that relationship between impacting tau is on its own, as well as relative to other covariates. That's something we absolutely will continue to assess in our larger Phase III as we move forward. Thanks, Diana. Let's go to the next one, please. We'll move next to Alex Hammond with Wolfe Research. Hi. Thanks for taking the question. Acknowledging you have to finish the end of phase II meeting with the FDA, when could we expect Biogen to come and disclose what the phase III design will be, and obviously therefore the start of the phase III? I guess, do we have to wait for the long-term extension to complete? Thank you. Go ahead, Diana. Yeah. Just to answer the first question, no, we don't have to wait for the long-term extension to complete. That just allows us to further characterize over time what the changes are. In terms of when, you can imagine, we're very busy thinking about and designing all the components of a phase III and pulling that information together. We're not prepared to give specific guidance on that today, but we'll certainly keep folks updated as we lock in that plan and engage with regulators. Yeah. Having an end of phase II meeting at earliest is of paramount importance. Absolutely. We're really working towards that, while in parallel, we're waiting to collect a little bit of that long-term data. This long-term extension goes beyond the 24 months for all patients. It actually goes out to two years. Absolutely beyond that. No, we wouldn't be waiting for that at all. The last thing to build on is while regulators are of paramount importance to us, you can imagine here at AAIC and subsequent to that, we're engaging very intensively with key medical experts, advocacy groups, patients and families that we understand we can design a trial and ultimately sort of launch a therapy, hopefully, that meets the needs that they have. There's a lot of voices that we're listening to and incorporating into figuring out the best possible phase III. Just regulatory approval is just one of our many goals. We are really looking ultimately to have a drug that will be meaningful to patients and prescribers. Great. Go to the next question please, Jess. We'll go next to Phil Nadeau with TD Cowen. Good afternoon. Thanks for taking our questions. Two from us. I guess first on the ADCS-ADL-MCI, any thoughts on why there was no separation in that endpoint? It is somewhat different than what we've seen for the beta amyloid antibodies. Second on the adverse dose response, is it possible that the increase in adverse events like confusional state at the higher doses could be obscuring some of the treatment effect on cognition and function, and that's why those doses don't quite measure up to the low dose? Thanks. Yeah. On the first one, I think on the ADCS-ADL-MCI, it's a great question. It is behaving in a pattern that is different from the other five endpoints. It's something we need to continue to examine over time. We haven't seen an effect yet. As I think I'd mentioned earlier in the presentation, it's something that we're wondering, is it something that could lag? We're not sure. We do believe, however, that function is being impacted because we are seeing in the CDR Sum of Boxes scores on function as well as on the iADRS composite endpoint with function, which incorporates function that we're seeing it. It does have a different pattern. We'll continue to examine it. We did see function in the phase I-B come in later. All good questions and hopefully over time that will become more clear. I think your other question was around the dose response. I think what we would just like to highlight again is that across all the doses, diranersen was favored. As Priya said, and that was across almost every endpoint with the exception of the one we just talked about. We do see that 60 mg looking optimal in terms of impact on these endpoints as well as tolerability. That idea of having a dose that's twice a year that's well-tolerated is an attractive proposition for us to be considering moving forward. Okay. Let's go to the next question, please. We'll go next to Jason Zemansky with Bank of America. Good afternoon. Thanks so much for taking our question, and congrats on the progress. I wanted to follow up on one of your earlier comments, but could you characterize the distribution of CDR-SB responses within the low-dose cohort? Were they relatively consistent or did we see a range across the participants? I guess what kind of supports the idea or the reproducibility of the observed benefits given its smaller size? Beyond the biological variables discussed, could some external issues such as selection of the sites have accounted for some of the variability that may have influenced the results? Thanks. Maybe we'll take that first question. We did show and break out for you on the podium slide, and we can send it back around if you don't have it. For the low-dose groups, ranging from 20%-42% on cognition and 21%-29% on function versus placebo. You can see that 60 dose group, how it performs compared to placebo, as well as how it performs compared to the mid-dose and the high-dose. That's on both cognition and function. Hopefully, you can see all that data that we showed. On sites and external, you can imagine we spend a great deal of time training our sites, and looking and clearing all the data. I think that is not something that we believe is an issue here. We're really trying to isolate what the sort of biology, biologically, how we're manipulating tau, and could there be a differential impact clinically. That's why the dose-ranging was designed actually to answer this question. Excellent. Let's go to the next one please, Jess. We'll go next to Myles Minter with William Blair. Hi. Thanks for taking the question. Congrats on the data. Just the cadence of discontinuations in the high dose, what was that? Did most people drop out in the first six months, or was it pretty even over it? I just wanted to clarify something you said about the confusional state cases in the high dose. I think you said mild to moderate, self-resolving, happened within the first few weeks. Presumably, that is happening well before you get material tau knockdown, as you've shown with your CSF and PET scan data. Just wanted to confirm that. Thanks very much. In terms of your first question, that's correct. Most of the AEs. The most common AEs were procedural pain or post-lumbar puncture syndrome, and then this confusional state, which had a higher incidence in the higher doses. Of the patients who experienced that, most were mild or moderate in severity, non-serious. You're right, it occurred pretty proximally to the lumbar puncture timing. Within seven days. Not weeks, but within about a week, and then resolved within about another week. Typically did not lead to study drug discontinuation. In terms of what that means, I think, yes, your point is very interesting, right? That would be too quick, because you can see from the biomarker engagement studies, it took time. It takes time, basically, for the ASO to stop the production, and then once the production has stopped, to see the resolution of the tangles. That would not necessarily line up with acute and reversible impacts on confusion. Definitely an area of study for us, but yeah, it is not something that's temporally correlated with tau reduction. I think it's time for two last ones. Maybe let's go to the next one, please, Jess. Certainly. We'll go to Yatin Suneja with Guggenheim. Hi. This is Delma for Yatin. Thank you for taking our question. Following up to previous questions on the baseline characteristics, did you identify any opportunity to enrich for a specific Braak stage or baseline tau PET cutoff or other parameters in phase III? Are you planning to include patients under treatment with LEQEMBI in phase III? Thank you. I think you had two questions. The first one was around baseline characteristics and overall Braak stages. As you can see, what we showed, and has been showed across others, is it was a tau PET sub study, we'll continue to sort of show the data. We had previously published what the baseline tau levels were. As noted, there is some variability. As well as everyone had their amyloid. We had this understanding of their amyloid sub studies as well. The majority of patients were in that 85- 95 Centiloids of amyloid. We have both tau and amyloid to examine over time. We'll be thinking about how to continue to characterize those moving into Phase III. It's something that I think we have a pretty good understanding of from ourselves, as well as the field, the sort of overall burden of both tau and amyloid in these mild AD and MCI patient populations. At this time, we won't consider any enrichment. Yeah. That's the other. I think it's probably, at this point, we wouldn't necessarily want to restrict ourselves to that enrichment because we're still understanding in the first place what engaging this target can do clinically. We'd rather sort of examine across MCI and mild AD, what impacting tau can do clinically. We want to gather all that data. We can have pre-specified subgroup analyses as part of our statistical analysis plan to help us look at the different cohorts. Overall, we would keep them. I think your last question was about LEQEMBI, right? Sort of the idea of co-administration. I think we said earlier in the webinar here, we're absolutely thinking about first and foremost, engaging on this tau monotherapy because we have to establish in phase III what the impact clinically is with this dose and, of course, safety and further characterization. We know that we're going, hopefully, to be launching into a field where patients are using potentially sequential or one at a time based on personalized biomarkers. Definitely a thought for us. Something that we're considering in a total development plan, how we'll be characterizing both. Must establish the monotherapy impact. Definitely thinking about a future state of sequential and combination as well and how we can develop data around those. Thanks, Diana. Jess, let's go to our last question, please. Certainly. Our last question comes from Jay Olson with Oppenheimer. Oh, hey. Thanks for providing this update and taking the questions. Based on the totality of data that you've now collected for LEQEMBI and diranersen, what is your current hypothesis on the relative contribution of amyloid versus tau to long-term disease progression? Separately, could you describe your clinical definition of the confusional state, and why does it seem to be dose-related? Would you consider it an on-target or off-target side effect of diranersen? Thank you. I can take that last part first, because I think we'd addressed it a little bit earlier. The temporal relationship of the confusional events being sort of within seven days of dosing and resolving within seven days after that would not be expected to sort of be consistent with the impact on tau. It takes time. Again, MAPT ASO is stopping the sort of We have to reduce the protein overall, and then we see by reducing the amount of protein, we see ultimately the clearance of the tangles in the brain. That temporal relationship is not something we would necessarily say is due to tau lowering per se. I think your first question was about the sort of how would we characterize the acute confusional sort of event. I think we had said mild to moderate, acute onset and resolving typically within a week. The last was about the relationship between amyloid and tau. It's a really exciting time to have multiple sort of mechanisms of action that we can see how they intersect with Alzheimer's disease. We're going to be generating our own data with LEQEMBI, looking at preclinical and seeing what manipulating amyloid preclinically is. Then we are also going to be, obviously here, some of the first people to see what over time, which long-term extension study will help us do, as well as a phase III, what the ultimate impact of reducing tau can do. Time will tell more of these stories across the entire sort of spectrum of Alzheimer's disease. What's exciting is to be at a time where hopefully we're able to sort of get at both amyloid and tau. Okay. Thank you all for the excellent questions. I mean, maybe I'll just close with a couple of comments here. I just want to point out that this is a very exciting data set for us. The reason that we are excited is that we are seeing a drug that is really hitting on a potential regulatory endpoint as well as cognitive endpoints, and on the cognitive endpoints, treatment effects that we haven't seen so far. We think we've isolated a dose that is emerging as a dose that could go into phase III. This drug also has the potential to be administered twice a year. I think it's supported by unprecedented biomarker data, specifically the tau PET data, which points to tau pathology reduction in the brain. While, yes, we didn't hit the dose response, we think that the data set is very encouraging with clear signals. We think that the data in totality really makes complete sense for us to forward this to phase III. That is what we're working with urgency on. I'm sure we'll be here to talk with you again and share updates as we make progress. I want to thank the team here that has joined me today. Thank you, Tim. Thanks, Diana. We'll end the call there. Reach out if you've got more questions. Thank you. Thank you. Ladies and gentlemen, that will conclude today's call. We thank you for your participation. You may disconnect at this time.