Good afternoon and welcome once again to TD Cowen's 2025 I&I Summit. I'm Phil Nadeau, one of the biotech analysts here at Cowen, and it's my pleasure to moderate a fireside chat with Biogen. We have with us today Diana Gallagher, who is the Head of Clinical Development of MSI&AD at Biogen. Diana, thanks for joining us today. I thought we'd start with maybe a few broad overview questions before diving into the programs in a little bit more detail. Just first, on I&I generally at Biogen, it's clear Biogen's reinvigorated its I&I efforts over the last couple of years. Why is Biogen's strategy and what is Biogen's strategy in I&I and kidney? Why does Biogen think it makes strategic sense to be in these areas? Sure. First of all, thanks for having me here, Phil. It's terrific to be here. For that first question, I think, you know, in a lot of ways, although people often think about us historically as a neuroscience company, I think our success in MS has really relied on deep expertise in immunology, more specifically neuroimmunology of the CNS. That really creates the groundwork upon which we're basing some of this. I'd mention too that we have had some of our work in lupus for a decade, decade and a half, we've been working on some of these. It's not brand new, I'd like to remind folks. The advantage, I think, of these drugs is in many ways to support a diverse product portfolio. By targeting these immunological pathways, these drugs often can be applied to multiple disease indications. Once we establish the safety and we understand how we're manipulating the biology, it allows us to sort of think about a multi-indication strategy, and that's quite attractive for us. Can you talk a little bit more about how you think an I&I R&D pipeline should be structured? What's the ideal spectrum of risk? Which therapeutic areas or diseases are attractive and which ones are not? Yeah, I think that one of the things we sort of like about immunology in particular is this idea of in these, you sort of always are led by the science, right? You can develop these, you understand that target that you're going after, you think about the biomarker strategy that you're going to leverage, you can bring it into sometimes pretty efficient early development trials, maybe even pick an indication that you think really allows you to answer that biological question very crisply, and you can use that to sort of expand out. Depending on the target, we may bring that into an indication where we sort of see like, hey, if we hit in this sort of, if we manipulate biology in this way, in this proof of concept, that gives us increasing confidence to expand into a multi-indication strategy. For some targets, we might start with two indications at the same time, and then that will, if we hit those, it ungates others. You see us sort of doing that with, well, felzartamab, I think pretty effectively. That is sort of the idea of how we're strategizing it. Based on our conversations, we suspect investors do not give Biogen much value for its immunology and kidney pipeline. Why do you think that is? What do you think investors are missing? Yeah, it's hard to know, but I think if you look at felzartamab, it's a really, I think, very carefully crafted sort of approach that exemplifies what I've just discussed. You have an anti-CD38 antibody, you have a very well-reasoned rationale of how it should manipulate biology in kidneys. You have a really unique indication of antibody-mediated rejection with a very robust biopsy endpoint. That was very efficient in an investigator-initiated study to basically say, hey, this really manipulates this biology, which gave us the confidence to then go into additional phase three studies with a lot of weight of evidence. Similarly, at the same time, take it into more indications where there was a more established traditional biomarker path and regulatory path in IgAN. We looked, and what's beautiful, you run a study like that, you look at the urine-to-protein creatinine ratio, you say, hey, I know if I hit that, that's going to translate into eGFR. I know what the regulatory path looks like for that. You really understand that sort of all the way from the dosing of the drug to hitting the biomarker profile to understanding what the product profile looks like pretty efficiently in both IgAN and pMN. I think that was three for three figuring that out, which was a really nice thing to see. Are there other indications that are yet to be announced that Biogen thinks felzartamab could work in? I know you can't tell us what the indications are, but are there other potential areas of application for anti-CD38? There definitely are, and I think there's a lot of folks thinking about those. One that we recently sort of articulated was the MVI, so not just the antibody-mediated rejection endpoint that we've already started our phase three, but sort of expanding into microvascular injury in the kidneys, which is on the spectrum towards full rejection. As you can imagine, the idea that we for a solid organ transplant are able to really meet that need and really attenuate rejection is important. That MVI, in addition to, I use a lot of acronyms, microvascular injury in addition to antibody-mediated rejection is one of the first things that we're pushing into and considering others as well. Great. Maybe turning to lupus, which you referenced, Biogen's been in for quite some time. Obviously, the late-stage pipeline currently has two candidates in it, dapirolizumab pegol and litifilimab. Historically, lupus has been a very difficult indication for companies to succeed in. Why does Biogen have confidence that it could succeed where these others have failed? Right. It's a great question. I think that our confidence is really data-driven. Maybe I'll start with litifilimab. That's a homegrown molecule that we brought forward, did a very detailed sort of 1B study back in the day where we had skin biopsies where we're really following that paradigm I just told you about. Do we manipulate biology? Do we understand how to pick the doses? We did that. We moved it into two proof of concept studies in the LILAC trial, which is sort of a combined trial, but we showed in back-to-back New England Journal articles back in 2022, here's how we're manipulating biology in SLE, an overall treatment effect, as well as showing good data on skin and joint. In CLE, which is an indication area that we've really been sort of committed to for a long time and are very proud of because there's no approved therapies for cutaneous lupus. We had POC there. That allowed us, really, those well-conducted early development studies, plus robust POC, allowed us to feel like we understood how to sort of move that we should and then how to move forward into what are two phase threes ongoing for SLE and then a two three for CLE. Very data-driven. I would also say you learn by doing. I mean, when we first started in lupus, we were all as a field trying to understand the clinical development paradigms, trying to understand the inclusion and exclusion criteria, trying to understand how should we manage the background medicines, how should we do the steroid tapering. A lot of clinical trial execution excellence in addition to having the right molecules. All of that, I think, has come around and kind of coming at the right time for us. For dapirolizumab pegol, we have a positive phase three. The confidence there comes from being a great target and a CD40 ligand, which broadly manipulates sort of biology, enrolling the right patients. It is moderate to severe lupus who've been actively flaring and designing a well-powered trial in the first PHOENYCS Go trial that we saw that said, hey, you hit the primary endpoint in BICLA. We were really happy to see we're affecting flares or reducing flares, which is really important to patients. We're seeing tapering of steroids, and we're seeing an improvement in fatigue. When you see all those things moving in a trial, it's an accomplishment. We're really happy to have, in collaboration with UCB, who's been a great long-standing partner for us with dapirolizumab pegol, really happy to have two different products to bring to bear, hopefully, in lupus. That's a great overview. Maybe to dive into each of the ongoing pivotal trials in a little bit more detail. At Biogen's recent earnings call, it announced that the TOPAZ- 1 and 2 trials in CLE have completed enrollment with data expected by the end of 2026. Could you briefly review the design of TOPAZ- 1 and 2? TOPAZ- 1 and 2 are SLE studies. So that's. Replicated? Yeah, no problem. Those are replicate studies in SLE of 540 patients each. Definitely excited to, these are large trials to recruit. They are both global studies where we're looking at patients who have systemic lupus. We sort of enroll patients who have a certain disease severity that we bring into the study. In that trial, we're testing two different dosing paradigms, which is administered subcutaneously once a month. We're just examining, our primary endpoint there is the SRI4, which is a composite endpoint, and we're also measuring BICLA. Those are as another endpoint. Those are overall sort of markers of improving disease control in lupus. We'll be looking at that. We have other endpoints, as I mentioned, looking at control in joints and impact on skin, as well as, of course, we're going to look at the steroids as well as multiple other endpoints. Large, replicate, global, well-powered studies to corroborate and impact on overall disease control with that primary endpoint. What do you think are the key risks to the trials? If they were to fail, why would that be? Yeah, I think we've been very intentional and very thoughtful about how we use the POC data to appropriately power, about that we're testing two doses. That is a good thing, I think, to do that dose ranging so that we will cover hitting the target and then understanding if we hit the target, will that manipulate biology and going into a representative sort of sample. I don't think we can do much, much more than that. Of course, as well as controlling the background medications, and then adjudicating the disease severity. I mentioned that I think historically lupus, it's not just having a drug and then putting it into patients who really have lupus. It's all this clinical trial execution pieces. It's a very high-touch, hands-on approach to executing these trials. I can't know if we got it all right, but hopefully we brought as much to bear as possible. Any thoughts as to what data needs to be produced on the key endpoints in the studies to make litifilimab a part of the standard regimen? Is statistical significance enough, or is there some specific quantitative level that you're hoping to achieve? Yeah, of course. We power them to sort of hit the primary as well as look at, like I mentioned, secondary endpoints that are meaningful to patients and providers. When we're looking at, well, patients want to, patients want first and foremost to feel better. This is a disease that is very debilitating, right? You have joint pain. You have often a lot of systemic symptoms, which can include profound fatigue, fevers, just sort of overall skin manifestations. Some of them have other sort of organ systems, which are flaring to certain degrees, and their kidneys. Some have cognitive issues with brain fog. It is a really multifaceted disease. These composite endpoints allow us to see, hey, on all these different endpoints, for this patient, are we manipulating your disease in a way that for these features which matter to you are overall, are we manipulating? I think, of course, we're going to look to see parity with, there's only two approved drugs so far. We are looking to see how we're performing against those. Also, we know the ACR guidelines are pushing. We want people on less steroids. If you're diagnosed at 20 years old, you can't be living on steroids till you're 70, right? They have major toxicities. Most patients, even on biologics, are not getting to lower limits of disease activity. There's more that they could do for overall disease control. Those that we're not getting good fatigue improvement. Those are all the features in this large replicate trials that we're going to be looking for. In cutaneous, which is the skin-predominant lupus, there we're sort of looking for almost like you do in other dermatologic diseases, so sort of percent reduction, right, in overall sort of amount of surface area, we'll call it for lack of a better word. There are endpoints like you see in psoriasis or atopic dermatitis where you say, can I get 50% improvement? Can I get 70% improvement? That has proven to be clinically meaningful to patients. Got it. Actually, could you go into a little bit more detail on the design of the Amethyst trial? How many patients enrolled? When do you expect to release data? Yeah. Amethyst is we had had the positive LILAC proof of concept, and now we're moving into this phase two, three. The first cohort, which we enrolled, was 90 patients. Now we're at the high- 300 in the mid -300s to up to 400. We're still sort of finalizing that and looking at that sample size for Amethyst. It'll be a robust study, one of the biggest cutaneous lupus trials ever conducted, which is great. We love that. It'll be in concert with having SLE data. I think we'll be able to look comprehensively and say, hey, we have these two nice SLE studies. We have this dedicated CLE study. Altogether, we really see how this is manipulating biology. We have thresholds for amount of cutaneous disease, which is sort of in that moderate to severe level. You have to have moderate to severe cutaneous disease to come in. And then we're looking at 70% improvement, 50% improvement. Those are the types of metrics that we'd like to see to say, hey, this biologic is helping you. Got it. Has Biogen discussed its filing strategy in SLE and CLE? Would you file the two indications independently? Would you file at the same time and hope to get a broad label? I honestly can't recall if that's something that Biogen is. I do not think so. Yeah, I think that is something that we are definitely thinking about how to optimize. We know that we have a single phase three in CLE. I think they are, as I mentioned, it is in concert. We will be thinking about them together. The exact way in which we are doing that, especially with the trials timing and what the best strategy is, we are still working through and should have, I think, next year some more thoughts about that. We are super excited to have gotten the SLE two trials enrolled. Now, hopefully, CLE will bring it around, finish enrolling that study, and then hopefully we will have a couple of different options and choices for how to approach it. Maybe moving to Dapi, you mentioned the PHOENYCS GO trial. For those less familiar, could you summarize the data from that positive phase three? Sure. That trial was enrolled patients, over 300 patients with moderate to severe, what we call active, sort of systemic lupus. It was very carefully sort of crafted to really make sure that we would bring these right patients in that even despite standard of care, and they were allowed to be on steady doses of standard of care, still had unmet need. We brought them into the study. We sort of had a fixed, and we do it in LEDA as well, steroid taper. We say, okay, we're going to get our drug on board. After a certain number of weeks, you have to start tapering your steroids so we can see if you're able to effectively do that. We also measured all the components I mentioned of overall disease control in every organ system using these composite endpoints. We measured fatigue. We measured overall disease activity scores. We were really looking very carefully across those over 300 patients to see if adding the CD40 ligand to disease, which was really not ideally controlled, could actually bring you into control. What you saw over time, as you look across that 52 weeks in that study, you saw that onset. You saw, hey, you overall see the impact on the BICLA, which is this composite score. We also hit on SRI4, which is a different composite score. You saw the steroids coming down. You saw the reduction in flares. You saw the fatigue scores improving. You see me, I keep moving my hands because they were, I just was so happy when they came back because directionally they track. A lot of the curves look similar, right? It did not switch out the endpoint, but you see the same effect. There was durability, right? Because it is a relapsing and remitting disease. These were people who were actively flaring. You want to see, yeah, even over a year, they might have burst through, right? They might have relapsed despite therapy, but we showed they had actually a 50% reduction in flares if they were on our drug. That was the top line. How does the design of PHOENYCS Fly compare to PHOENYCS Go? Are there any notable differences? No. It's very similar. I think that, of course, we look at the data and learn from it, but essentially it's going to be looking at that BICLA. It's going to be powered effectively to do that. The one thing that we did mention, and it's in the public domain, one of the things you never know, particularly in moderate to severe disease and as you're manipulating steroids up and down, when will the treatment effect come on? Our first primary was the endpoint at week 24, and we just missed. We're thinking about that. It's really overall disease control as opposed to, so that's something we're kind of thinking through. Honestly, they were designed to be replicate. They're quite similar. Yeah. Has Biogen guided to when PHOENYCS Fly could read out? I think we are designed, I think at Chris probably in pre-ad earnings, where it's 28. Yeah. Okay. Okay. Again, any thoughts there? What type of data needs to be produced to put dapirolizumab pegol into the standard regimen for the treatment? Yeah. I mean, we'd love to see that replicate that PHOENYCS Go data, not on the primary. And it's a yes and answer for those other components, the flare reduction, the fatigue, and the steroid sparing. Even as we're designing, you can see that the American College of Rheumatology keeps pushing us to try to get, no, get them on five. It used to be if they were down to 7.5 mg of prednisone, that's good enough. Now they're like, no, five. There's really this push because of the consequences of long-term steroids for these patients that they want them on as low a dose as possible. We're going to be looking at all those. Can we reduce flares, reduce fatigue, reduce steroids, and hit the primary? That is helpful. Maybe in the last couple of minutes, Biogen unveiled a new program recently, BIIB142, the IRAK4 degrader. Could you provide a brief introduction to that program? How can IRAK4 degrader be differentiated, and for what autoimmune diseases could it be most promising? Yeah. What intrigues us about that target is probably, and that asset in particular are two things. IRAK4, we know, plays a key role in inflammation. This is an oral molecule. It is actually a slightly different modality in that it is a degrader. It is complementary in that it is a different mechanism of action and a different presentation in an oral molecule. Where we could take it is that sort of a fun thing when you are in immunology because you could take it into lots of different things. The first thing we need to do, of course, in the Healthy Volunteer study is just kind of get our bearings with the PK and the PD and then continue to look at the types of, we could take it into multiple autoimmune conditions. We are contemplating all manner of those. You could imagine, of course, we might think about how could this look potentially in a lupus portfolio, but we could also bring it into other places as well. We have not locked in the final, but hopefully it is a multi-indication strategy if we can do it the right way. We will sort of update as we go of where we are going to put that. Yeah. Great. Has Biogen said when the phase one data could be released? We haven't. Yeah, we're just getting going. Yeah. Great. We covered a lot of your I&I and kidney programs, but is there anything we haven't discussed that you'd like to highlight? Any other programs that we haven't brought up that you think are particularly promising? I think we definitely continue to build out our early stage pipeline, and hopefully we have been fortunate enough to bring in even more immunology research expertise to Biogen. You saw us, we did the Ventyx deal where we brought in that C5 asset. Hopefully, we'll continue to bring in potentially other particularly preclinical assets into our portfolio so we can collaborate and do more of this work. Of course, also on the kidney side, we definitely have a follow-on anti-CD38 because it tells us amazing, but there are other places, as you indicated, we could take it. Whether we choose to do that with a front-runner asset or with a next-gen type of follow-on anti-CD38 is also under consideration. Those are some thoughts. Yeah. All right. With that, I think we're out of time. Thanks so much for joining us today. We really enjoyed the overview and the discussion. My pleasure. Good to be here. Thank you. Thanks.