Conference Transcript - BIIB 2026-07-14

Operator

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 and AAIC 2026 webcast. All lines have been placed on mute to prevent any background noise. After the speaker's 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 1 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.

Tim Power, Head of Investor Relations

Thanks, Jess, and 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 list factors discussed in our SSE filings for additional Joining me on today's call are Dr. Priya Singel, Head of Development, and Dr. Diana Gallagher, Head of Clinical Development for Immune-Mediated and 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. And I'll now hand it over to Priya. Good afternoon.

Priya Singhal, Other

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 Likambi iClick for treatment initiation for early Alzheimer's disease. We at Biogen have chosen to tackle Alzheimer's disease for several years. And 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 DiraNursen, which we believe demonstrates an important advancement in targeting TAO. The CELIA study was a pioneering effort. What we have observed is that Dirin-Ursson 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 and therefore identify a dose to advance into phase 3 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, pyrinocin being favored for all doses, showing consistency across the data set. Three, the 60-milligram dose twice a year, demonstrating the largest and most substantial benefit across nearly all endpoints. And finally, the results that reinforce the prior findings from the smaller Phase I-B Furthermore, not only did we see ACDR 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. Dear Nursing now has the potential to be administered just twice a year and has a mechanism that is not associated with ARIA. Now, let's walk through what we have learned from Celia with Diana.

Diana Gallagher, Other

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. As far as you know, antibody approaches have not been successful in showing clinical benefits. 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, deirinersin 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. So now 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 deer inerthus. We measured several clinical endpoints, including CDR from a box, 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. So now 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. As you know, we did not meet and observe that dose response pattern in this trial. Importantly, as shown on this slide, cirinusin was favored over placebo across nearly every endpoint, though, which is very promising. So 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 effects at the 60 milligram 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 therapies. And when we dig deeper into the data for that 60 milligram dose, we see a very compelling profile emerge. On this slide, we replaced the 60 milligram data from today's AIC presentation into context alongside results from historical amyloid therapy trials. While these are not head-to-head comparisons, we believe they are useful for thinking about our decision to move deer nursing forward to phase 3. Recognizing the sample size limitations of a phase 2, what we are seeing is that the benefit on CDRS-B is similar to anti-amyloids, but with a greater effect size on cognition than what we have seen with other agents. For example, we observed 42% for ADAS-COS-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. But importantly, we will continue to follow patients and look forward to seeing how this evolves over time, including looking at 24 months. And 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. And that's because when we examine the individual components of the CDRS-B, the benefit is not driven solely by cognition, but is also evident in the functional domain. As you may recall, CDRS-B consists of six domains, and the top three on this slide assess cognition. and you can see consistent treatment effects against each of those measures. But 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. So 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. And 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 of 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 DERA-Nursen arms, cow pathology accumulation was not just low, but reduced from baseline. This has never been seen before with any other cow-directed agents, and in our view, this is a very important finding. Turning now to safety, what's important to note is that DERA-Nursen was well-tolerated in this daily study, with no new safety signals identified as compared to our FACE 1D. 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 1B, confusional state was reported as an adverse event, and there was a higher incidence of confusional state AEs observed at those higher doses. But importantly, RA, which was not anticipated with this mechanism of action, and the results and 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 up the discussion.

Priya Singhal, Other

Thanks, Diana. I would now like to address what is next for DiraNursen. 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. And 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 DiraNursin to Phase III is the appropriate next step. We're now working urgently towards a phase three 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 three 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 Dirin Nursen, 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. And 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, dozing continues in the LTE, and we have the opportunity to continue to learn more about Direnperson, including the two-year data. I hope that the review today helps you appreciate why we are excited about Direnursen's overall potential to be the first tower targeting medicine for early Alzheimer's disease and the reasons that we are advancing it to phase 3. Tim, please go ahead and open the call for questions.

Tim Power, Head of Investor Relations

That's great. Yes, can we go to the first question, please?

Operator

Certainly. Thank you. If you would like to ask a question, please signal by pressing star 1 on your telephone keypad. Again, then a star 1 to ask a question. We will move first to Evan Siegerman with BMO Capital Market.

Evan Siegerman, Analyst — BMO Capital Markets

Hi, Priya and Tim. Thank you so much for taking my question. As we look at the data, is it possible that, you know, you're not, you're, you're, is it possible that we're knocking down tau too much at the high doses to not get an effect? And how do we know the 60 milligram dose is the right dose to take forward? You know, 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. So long way of saying, is 60 milligram the right dose to be taking forward? Should we be looking at lower doses here? Thank you very much.

Priya Singhal, Other

Thanks, Evan. I'm going to turn that over to Diana.

Diana Gallagher, Other

Thanks, Evan, for the question. So, yes, I mean, one of the reasons we moved from phase 1b, where we had, in a small sample size, tested some of these dosing paradigms to a dose-ranging phase 2b, was to answer the exact question you're positing there, and to determine, do we have a path to phase 3, and what is the dose? What we see in that 60-milligram dose, I think, is that we see the reduction in the tau CSF as well as the reduction in the tau tangles, which corroborates what we've seen in phase 1B. And we see it across every endpoint that we measured, the key secondary endpoints, with the exception of the ADS-MCI. And so that's really encouraging to us. In terms of assessing whether or not, you know, that we have the dose in its totality, right? You see this also, Darren Arson is favored across every dose, but our goal here was to identify the dose or the emerging dose that we take forward into phase three. And we think that's what we've done here.

Tim Power, Head of Investor Relations

Thanks, Tylee. Let's go to the next question, please, Jess.

Operator

We'll go next to Salveen Richter with Goldman Sachs.

Salveen Richter, Analyst — Goldman Sachs

Good morning. Thanks for taking my question. When we look at the 60-milligram dose arm, you know, the N was small here. There were a lower amount of patients with APOE4, and, you know, there were fewer women in that cohort and lower amyloid PET potentially. So I guess what I'm trying to ask is, you know, 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 3 trial, and the thoughts of doing a combo with amyloid in Phase 3. And if I could just also add, what's driving the confusion state?

Diana Gallagher, Other

There's a couple questions there, maybe we'll take them in order. And I think the first one had to do, you know, with understanding what we're seeing in this group of context study. And it is acknowledged that, you know, we were testing three different dosing paradigms versus placebo in that two-to-one to two-to-two. And so, we think we had nice, you know, overall distribution, you know, in the baseline demographics. But, of course, it's never going to be identical. And we think that when we're looking at that, we see effect sizes that, you know, are pretty comparable across. We've started to look at some subgroup analysis. We will be presenting that in the future, but, you know, 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 three, 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, you know, our phase three? You know, it's a great question, and it's something, of course, we'll be engaging with regulators about in the coming weeks and months. And 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. So we will be, you know, engaging with them to understand what is necessary, you know, from a sort of dosing standpoint, as well as safety and ultimate efficacy in order to meet expectations there. And so we're really excited about what's happening in particular. And we also know that we will be hopefully engaging in a market that continues to have utilization of multiple sort of drugs. So we're thinking just as you are about, you know, future states where patients based on their personalized biomarkers may sort of use drugs at the same time or sequentially and, you know, more to come there. But right now we're focusing first and foremost on the cow monotherapy and then thinking about adjunctive data.

Priya Singhal, Other

And finally, I think you had a question, Salveen, about the confusion event.

Diana Gallagher, Other

Sure. So, as we mentioned, you did see that there was an increase in confusion in a dose-responsive way that Kath Mamrie 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 choose. So, 94% of patients who are eligible rolled over into long-term extension, which was a question we didn't know, you know, from an intrathecal standpoint, how would patients and families react to this? So, we're seeing a lot of retention for this drug and the threat of administration, which we think is encouraging as we move towards it.

Tim Power, Head of Investor Relations

Let's go to the next question, please.

Operator

We will go next to Eric Schmidt with Cantor.

Eric Schmidt, Analyst — Cantor

Thanks for the very efficient call. Well, maybe given this is a bit of a smaller phase, too, how did you guys convince yourself that the placebo group is not behaving apparently? Any comparisons you might have looked at would be helpful? And then I know there's 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?

Diana Gallagher, Other

Sure. So generally, in looking at placebo, acknowledging this is, as you said, a small study and cross-study comparisons are challenging. You know, we see it's generally consistent with trials, our sort of peer trials with mild Alzheimer's or MCI. So, for example, we see the CBRFC, you know, 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. And I think you had a second part of your question, which had to do with the higher dose discontinuation. Yeah, 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. So that's something we'll continue to study. But again, the fact that we had high completion rates for an Alzheimer's study, particularly one that's intraday-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.

Priya Singhal, Other

And I think we're really pleased with the emerging dose and its benefit profile, right? Because we're seeing very consistent rates of adverse events and rates of discontinuation. So that remains quite promising.

Tim Power, Head of Investor Relations

So the next question, please, Jess.

Operator

We'll go next to Michael DeFore with Evercore, excuse me, with Evercore ISI.

Michael DeFore, Analyst — Evercore ISI

Hi, guys. Thanks so much for taking my questions. Number one, what could explain the disconnect between towel lowering and clinical response? You think that the PD effect and clinical response would be positively correlated, but we saw the opposite. And also, why do we see cognitive benefit but no clear functional benefit on ADCS-ADL? And just one more, why would you say the decrease or benefit on MMSC was so much higher than it was on CDRSB, especially when CDRSB is generally considered to be a more sensitive measurement. Thank you.

Diana Gallagher, Other

So we'll work to take those in order. And I think one of the first things I want to do in terms of how 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. So we're going to continue to assess, you know, all of the different components of that as we 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? So 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 looked at week 37 and then week 100. We did see there, actually on FAQ, that it wasn't moving very much at 37, and then we started to see it at 100. So one of the reasons we have a long-term extension is continue to see if any of these endpoints, which aren't behaving maybe as we would initially expect, change over time. Over time, the composite endpoints was because they have function in them. So as you saw on the podium, the CDRSV has both cognition and function, And we do see a dose response, similar to what we saw with the other endpoints, on function. So 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 CDRSC as well as on the IADRX. So that was why this weight of evidence across multiple endpoints, two-secondary endpoints, is how we got confident that, you know, by targeting tau, we're seeing this. I think your last question was, why would there be a disconnect? And, you know, that's a great question. We're pleased to see the impact on CDRS-B, you know, at that level that we are seeing and on cognition and function, like MMS-C, you know, and ADAS-COP for cognition. It's really quite remarkable in cross-study comparisons. So it's something we're kind of at this pioneering space. We're definitely seeing a significant impact on cognition alongside. We'll continue to examine over time whether they remain comparable or continue to have this pattern. But I want to emphasize that it's in both cognition and function.

Priya Singhal, Other

I'll just add that CDRs, some of the 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 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. And I think what's really encouraging about MMSC is that it is a test that physicians administer in the office. And seeing such a treatment effect at the 18-month time point is really encouraging. But 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. So, you know, 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.

Tim Power, Head of Investor Relations

We'll go to the next question, please.

Operator

We'll go next to Paul Matias with Stifol.

Paul Matias, Analyst — 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, and I guess just more broadly, it sounds like you don't want to speculate on the mechanism of the inverse dose response, but at this point, are you, like, would you say you're convinced that there isn't some on-target tox when you lower tau too much? Thank you.

Priya Singhal, Other

Yeah, we have. 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. And I would say that, you know, it's possible. I think, you know, there are several hypotheses as to why a higher dose may not actually translate to clinical efficacy. But 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, you know, tau does have a role in the normal physiology of the brain, microtubules and neurons. So all of this is possible, but I think we are really encouraged and excited by the fact that we've isolated the dose here.

Tim Power, Head of Investor Relations

Thanks, Priya.

Tim Power, Head of Investor Relations

Let's go to the next question, please.

Operator

We will go next to Terrence Flynn with Morgan Stanley.

Terence Flynn, Analyst — Morgan Stanley

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 one. And then on the phase three design, how are you thinking about the primary endpoint? I know when you did the cell side call several weeks ago, you weren't committing to CDR some of boxes. And now that we've seen some of the other secondary endpoints, looks like the effect size might be more dramatic. So any preliminary thoughts on how you're thinking about primary endpoint for phase three? Thank you.

Diana Gallagher, Other

Turning to your first question first on the phosphorylated cow endpoints, we are analyzing that data and we're looking at it, but haven't disclosed it yet. So we have a lot more data that we're going to be disclosing in the coming 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 the world, and I think we have not, you know, finalized what that will be. We do see an effect on CDRSC, which was, you know, one of the important things that we wanted to do here. We also see it on IADRS. We also see it on cognition. So, again, this weight of evidence, we have, you know, across multiple endpoints, gives us the opportunity to engage in that dialogue, but we have an understanding, particularly in the U.S., of typically what their expectations have been, and so we'll have that conversation with them.

Priya Singhal, Other

And maybe we can offer that we have looked at PTAO 181. We know that it's consistent, and, you know, we haven't shared details, but we look forward to sharing that.

Tim Power, Head of Investor Relations

Let's do the next question, please, Jess.

Operator

We'll connect to Michael Yee with UBS.

Tim Power, Head of Investor Relations

Thank you, guys. Two questions.

Michael Yee, Analyst — UBS

One is, do you believe that the tau reductions are basically pretty much all the same in overlapping confidence intervals on the doses? And so maybe all of those doses pretty much give you the same result. And so 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 iAddress. So, to me, it looks like only CDR, some of the boxes, is a standout, but all the other ones basically overlap, particularly iAddress. So, do you agree with that comment, and would you be open to using iAddress, which is arguably a potentially better endpoint for phase three?

Diana Gallagher, Other

It's possible, and we're examining the data, you know, as you said, and thinking about engaging with regulators. Again, we'd like to point out, we do see that impact on CDR, some of BASA's, as well as the eye address. And so seeing it in both places gives us that, you know, optionality and flexibility, which we're encouraged by. And to sort of toggle back to your question, is it true? You know, it is true. There was a robust impact, you know, on the tau biomarkers, both in the lowering in the CSF, as well as the impact, you know, across the tau PET. And so, you know, we continue to examine that data as well. But you're right, we saw very robust sort of target engagement and reduction of tau tangles across all the doses, which was absolutely encouraging.

Priya Singhal, Other

And we do think that a lot of those confidence intervals overlapped. So, you know, we think that it is it's hard to say that there was a dose response on the tau reduction. The second thing I would just say about IDRIS and CDR Summerboxes, I think that we are, I just want to be clear that we do believe that there is 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. And so we'll have to see how that evolves. But as of now, we believe that low dose is distinguishing itself. And so that's important. And I think IDRIS 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 and consistently better at the lowest dose. So there may be an overlap in some, but we think that the lowest dose is distinguishing itself. And actually for CDRs, some of boxes, even the absolute change at the 18-month time point of about 0.54 is quite impressive. So, you know, we're continuing to see whether that evolves. But, yeah, we think the large dose is declaring itself.

Tim Power, Head of Investor Relations

Thanks, Priya. Let's go to the next question, please, Jess.

Operator

We'll go next to Chris Shaw with J.P. Morgan.

Taylor Hanley, Analyst — J.P. Morgan

Hey, this is Taylor Hanley on 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 dyrinurcin versus Lakembi and Kassanla, just when you're comparing both their efficacy and their safety profile? Thank you.

Priya Singhal, Other

Sure. It's a great question, and it's one that we've thought about. I mean, just stepping back, you know, we know that about 6.5 million patients have Alzheimer's 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 continue to, this market continues to develop. And specifically as blood-based biomarkers come in, we think that diagnosis rates will increase. The important thing to remember about an anti-tao 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. So 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. And as Diana mentioned, who may be typed on a different biomarker profile and would be suited to different options. For example, you know, while the CDR sum of boxes at the 18-month time frame is consistent with the anti-amyloids we haven't yet seen, the two-year data, and we know that the other cognitive endpoints are orders of magnitude different. So how will all of this evolve at 24-month time point? What will the phase 3 show? And how will we design that phase 3? Those are the questions that we're trying to tackle. But we think there is an important role for a therapeutic modality that tackles itself. And I think that we are also looking and very cognizant of the fact And if we're successful in phase three, we would launch into a space that does have anti-amyloid treatment. So 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 treatment paradigms? So I think it's the totality, but we think this is a large opportunity. So obviously a few years away, we're just at the threshold of starting a phase three. So a lot of work ahead of us, but we believe it's going to be an important and exciting opportunity.

Tim Power, Head of Investor Relations

Let's go to the next question, please.

Operator

We'll go next to Mohit Benzal with Wells Fargo. Your line is open. Please go ahead.

Diana Gallagher, Other

Hi, this is Fadi Rahman on from Mohit. Thanks for taking the question. And just wondering if you've looked into any subgroup analyses here yet, and if that might give you more confidence that any of the, you know, the small baseline imbalances, for example, on CDRSV or CDR global scores here, you know, might not be driving any differences in these responses between the different doses.

Alex Von Riesen, Analyst — Piper Sandler

Thank you.

Diana Gallagher, Other

So, it's a great question. And we showed the sort of overall demographics of the patients and, you know, the differential and the different dose groups. It's pretty well done for a small sample size, but you called out a few small changes. I think, you know, due to time constraints, we weren't able to show everything, and that analysis, subgroup analysis is ongoing. But what I can say is based, you know, on what we've been looking at so far, we're seeing efficacy across those patient profiles. So we're obviously ultimately going to, you know, consider presenting those things. But there's nothing that we're really seeing differentially at this time.

Priya Singhal, Other

And I think overall we're just seeing very consistent overall trends. We've also looked specifically at some very important subgroups like, you know, the A4E4 carriers.

Speaker 19

And we know that there's a differential in terms of, you know, can anti-amyloids, are they being used to treat that population? and actually we see consistent trends across small numbers in a small trial but quite consistent trends let's go to the next question we'll go next to andrew sai with jeffrey thanks for the update um it's pretty obvious that the logos is doing the best out of three arms but a bigger picture question could be that um can you guys name uh some cns neuro drugs that have succeeded clinically and commercially despite having a rapid dose response. Just wanted to get a sense of how common actually this phenomenon might be in CNS. Thank you.

Priya Singhal, Other

We couldn't understand the question. We heard your first part where you acknowledged that the lowest dose does best, but we didn't hear the question. Can you repeat it slowly?

Tim Power, Head of Investor Relations

I'm going to mute your line.

Diana Gallagher, Other

What I think I heard was that is there precedent in other CNS tests that have been shown, you know, shown a dose response. And I think there are certainly examples where, you know, efforts are taken to examine whether or not, you know, a pre-specified dose response is met that hasn't necessarily been seen, but the efficacy shown allows you to move to phase three. And so here, again, this is the first time anyone's early 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. And so 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? So it's really that go forward position, the confidence in identifying that dose. I hope that answers what we thought we got most of your questions.

Priya Singhal, Other

I'll just add that we also were taking this assumption from the anti-amyloid, which have really been the only successful drug development program for Alzheimer's disease. But there is a fundamental difference. With amyloid, we're looking to clear all of it. And 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. So, you know, 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.

Operator

We'll go next to David Amselam with Piper Sandler.

Alex Von Riesen, Analyst — Piper Sandler

Hi, good morning. This is Alex Von Riesen on for David. Thanks for taking our question. We wanted to briefly touch on the Alicone acquisition you made last year. You've previously said that you were exploring the device for Spinraza, but we're just wondering if Biogen has an appetite to use the device for DeraNursin, and how do you think this may change its role in the treatment landscape relative to a traditional intrathecal and other IV or subcutaneous options?

Diana Gallagher, Other

Yeah, it's a great question, and that Secaflex device, as you said, from Alcian is something that could be an option that we could build into as we're thinking about, you know, designing the phase three, which is, as Priya said, is still under development. And for patients with Alzheimer's, they may, particularly for a twice-yearly administration, want to have different options. For some patients, they might say, you know, going to the doctor and having, you know, introsecal twice a year is fine. Others may say have complex spine, or they may just say, their families may say, if I can have the option of, you know, an indebellum catheter, that just makes things easier. So what's great is that, you know, hopefully we can have the opportunity to offer for patients and families the decision to make on their own.

Operator

We'll move next to Emily Field with Barclays.

Emily Field, Analyst — Barclays

Hi, thanks for changing my question. And I guess I wanted to follow up, Priya, on one of the answers you just had about, I guess, targeting that tau sweet spot, I guess, because dear nurse lowers tau indiscriminately you know with the physiological and pathological is is that what creates that sort of 50 i guess feeling on lowering tau and do you think that that's as far as you can go without impacting the physiological tau and then secondly um you flagged baseline tau variability as a possible driver uh between um some of the uh cognitive outcomes that you showed today, and I was just wondering, you know, if you're planning on including baseline tau as a stratification factor in the phase three, or how you plan to explore the impact of that in the future? Thank you.

Priya Singhal, Other

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 two. What we know from the biology, we were never looking to clear all the health. That was never the goal. And 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. Is it possible that 60 milligrams twice a year gives us that sweet spot? And so we're really happy that we have been able to identify that in Phase 2, which was really a dose-finding study. So, 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 3, I'm going to turn it to Diana. We are thinking about this very deeply.

Diana Gallagher, Other

Yeah, so 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 he 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. So, that's something we absolutely will continue to assess in our larger phase three as we move forward.

Tim Power, Head of Investor Relations

Thanks, Hannah. Let's go to the next one, please.

Operator

We'll move next to Alex Hammond with Wolf for research. Hi. Thanks for taking the question.

Diana Gallagher, Other

So, acknowledging you have to finish the end of phase two meeting with the FDA, When could we expect Biogen to kind of disclose what the phase three design will be, and obviously, therefore, the start of the phase three? I guess, do we have to wait for the long-term extension to complete? Thank you.

Priya Singhal, Other

Go ahead, Diana.

Diana Gallagher, Other

Yeah, so 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. And then in terms of when, you know, you can imagine we're very busy. like thinking about and designing all the components of a phase three and pulling that information together. So we're now prepared to give specific guidance on that today, but we'll certainly keep folks updated, you know, as we lock in that plan and engage with regulators.

Priya Singhal, Other

Yeah, and having an end of phase three meeting at earliest is of paramount importance. So we're really working towards that. While in parallel, we're waiting to collect, you know, 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 beyond that. So, no, we wouldn't be waiting for that at all.

Diana Gallagher, Other

Just the last thing to build on is, well, you know, regulators have paramount importance to us. You can imagine here, you know, at AIC, and subsequent to that, we're engaging very intensively with key medical experts, you know, advocacy groups, patients and families to sort of, so that we understand, you know, we can design a trial, you know, and ultimately sort of launch a therapy, hopefully, that meets the needs that they have. So, if there's a lot of voices that we're listening to and incorporating into, you know, figuring out the best possible things.

Priya Singhal, Other

And 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.

Operator

We'll go next to Phil Nadeau with T.D. Cowan.

Phil Nadeau, Analyst — T.D. Cowan

Good afternoon. Thanks for taking our questions. Two from us. I guess first on the ADCS-ADAL-MCI, any thoughts on why there was no separation in that endpoint? It is somewhat different than what we've seen for the beta-amyoid antibodies. Then second on the inverse-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.

Diana Gallagher, Other

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, so it's something we need to continue to examine over time. And we haven't seen an effect yet. As I think I 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 CBR some of the scores on function as well as on the IADRS composite endpoint with function, which incorporates function that we're seeing it. So it does have a different pattern. We'll continue to examine it. We did see function, you know, in the phase 1B coming later. So all those questions, and hopefully over time, you know, that will become more clear. And I think your other question was around, you know, the dose response. And so I think, you know, what we would just like to highlight again is that across all the doses, dear nurse, and it was favored, you know, and as Priya said, and that was across almost every endpoint with the exception of the one we just talked about. But we do see that 60 milligram looking optimal, you know, in terms of impact, you know, on these endpoints, as well as tolerability. So that idea of having a dose that's twice a year, you know, that's well-tolerated, you know, it's an attractive proposition for us to be considering moving forward.

Tim Power, Head of Investor Relations

Okay, let's go to the next question, please.

Operator

We'll go next to Jason Zemansky with Bank of America.

Jason Zemansky, Analyst — 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 CDRSB responses within the low-dose cohort? I mean, 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? And then I guess beyond the biological variables discussed, could some external issues such as like selection of the sites have accounted for some of the variability that may have influenced the results? Thanks.

Diana Gallagher, Other

So maybe we'll take that first question. We did show and break out for you on the podium side, and we can send it back around if you don't have it. But for the low-dose groups, slowing ranging from 20% to 42% on cognition and 21% to 29% on function versus placebo. And so you can see that 60-dose group, how it performs compared to placebo, as well as how it performs compared to the mid and the high dose, and that's on both cognition and function. So hopefully you can see all that data that we showed. And then on sites and external, you can imagine we spend a great deal of time training our sites and looking and querying all the data. So I think, you know, that is not something that, you know, we believe is an issue here. We're really trying to isolate, you know, what the sort of biology, biologically, have to be a differential design actually.

Tim Power, Head of Investor Relations

Let's go to the next one, please, Jess.

Operator

We'll go next to Myles Minter with William Blair.

Myles Minter, Analyst — William Blair

Hi, thanks for taking the question. Congrats on data. Just the cadence of discontinuations in the high dose, like what was that? Did most people drop out in the first six months? So was it pretty even over it? And then 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.

Diana Gallagher, Other

So 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, you know, in the higher doses. But of the patients who experienced that, most were mild or moderate in severity, non-serious. And you're right, it occurred pretty proximally to the lumbar puncture timing, so within seven days, not weeks, but within about a week, and then resolved within about another week. And so 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, you know, engagement studies, it took time. It takes time, basically, for the ASO to stop the production. And then once the production is stopped to see the resolution of the tangles, that would not necessarily line up with acute and reversible, you know, impacts on confusion. So definitely an area of study for us. But yeah, it is not something that...

Tim Power, Head of Investor Relations

We think it's time for two last ones. Maybe let's go to the next one, please, Jess.

Operator

Certainly. We'll go to Yatin Sunija with Guggenheim.

Delma, Analyst — Guggenheim

Hi, this is Delma for Yatin. Thank you for taking our question. So, following up to previous questions on baseline characteristics, did you identify any opportunity to enrich for a specific BRAC stage or baseline tau-pet cutoff or other parameters in phase three? And are you planning to include patients under treatment with LeCambi in phase three? Thank you.

Diana Gallagher, Other

So, I think you had two questions. The first one was around baseline characteristics and overall BRAC stages. So, as you can see, what we showed, you know, and has been showed across others is it was a TauPET sub-study, and so we'll continue to sort of show the data. And we had previously published what the baseline Tau levels were, and as noted, there's some variability. As well as everyone had their amyloid, we had this understanding of their amyloid sub-studies as well. And the majority of patients were in that 90, you know, 85 to 95 centaloids of amyloid. So we have both tau and amyloid to examine over time. And so we'll be thinking about how to continue to characterize those moving into phase three. But 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.

Priya Singhal, Other

And at this time, we won't consider any enrichment.

Diana Gallagher, Other

Yeah, I think it's probably, you know, at this point, we wouldn't necessarily want to restrict ourselves to that enrichment because we're still understanding in the first place what targets, you know, can do clinically. And so we'd rather MCI and mild AD, what, you know, impacting cow can do clinically. So we want to gather all that data. We can have a different cohort. The last question was about Lakembi, right, and 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 three what the impact clinically is with this dose and, of course, safety and further characterization. but we know that we're going hopefully to be into a field where potentially sequential or one at a time based on personalized biomarkers so definitely a thought for us something that we're considering in a total development plan how will we characterize in both so must establish the monotherapy impact definitely thinking about a future state of sequential and combination as well and let's go to our last question please Certainly, our last question comes from Jay Olson with Oppenheimer.

Jay Olson, Analyst — Oppenheimer

Oh, hey, thanks for providing this update and taking the question. Based on the totality of data that you've now collected for Lakembi and DERA-Nursen, what is your current hypothesis on the relative contribution of amyloid versus tau to long-term disease progression? And then 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 deer and nursing? Thank you.

Diana Gallagher, Other

I can take that last part first because I think we addressed it a little bit earlier. The temporal relationship of the confusional event 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, mass TASO is stopping the sort of moving that we have to reduce the protein overall. And then we see by reducing, you know, the amount of protein, we see ultimately the clearance of the tangles in the brain. So that's temporal relationship. You know, it's not something we would necessarily say due to tau luring per se. And I think your first question was about the sort of how would we characterize the Q-infusional sort of event was about the relationship between amyloid and TAV. And it's a really exciting time to have multiple sort of mechanisms of action that we can see how they intersect. We're going to be generating our own data with Likambi, looking at preclinical and seeing what manipulating amyloid preclinically is. And then we are also going to be, obviously, here, some of the first people to see which long-term extension study will help us do, as well as a phase three.

Delma, Analyst — Guggenheim

Across the entire, you know, hopefully we're able to sort of.

Priya Singhal, Other

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. And 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 safe space. It also has the potential to be administered twice a year. and I think is supported by unprecedented biomarker data, specifically the TauPET data, which points to Tau pathology reduction in the brain. And so while, yes, we didn't hit the dose response, we think that the data set is very, very encouraging with clear signals, and we think that the data in totality really makes complete sense for us to forward this to phase three. And so that is what we're working with urgency on. And I'm sure we'll be here to talk with you again and share updates as we make progress. So I want to thank the team here that has joined me today. Thank you, Tim. Thanks, Diana.

Tim Power, Head of Investor Relations

And we'll end it all there. We try to get more questions.

Operator

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.