Welcome to day three of our London Healthcare Conference. I'm Andrew Tsai, Senior Biotech Analyst at Jefferies, and it's my pleasure to have Doug Love, President and CEO of Annexon. Welcome, Doug. I guess in the interest of time, maybe spend a couple of minutes talking about the Annexon story, what you're working on, what kind of milestones we can expect over the next 12 months. Yeah, thanks again, Jefferies, for having us. We're delighted to be here. Annexon's working on a next-generation complement platform. You guys are probably familiar with downstream complement approaches targeting C3 and C5. What's unique about our approach is we're targeting neuroinflammatory cascade right where it starts at the source of disease. As a result, we're seeing differentiated outcomes in a host of different diseases from a functional perspective, whether that's vision, muscle strength, cognition, et cetera, and many, many diseases, which is quite encouraging. Ten years into our journey now, we're led by two late-stage programs, one Guillain-Barré syndrome with the landmark WIN phase III program, for which we're now pursuing regulatory approval across the globe. Secondly, geographic atrophy, really an outsized program, 8 million patients with geographic atrophy. This is the only program to demonstrate significant vision preservation on every endpoint, which is really important from a vision perspective, as well as significant protection against photoreceptor cells, which are the neurons in the eye responsible for vision, yet another differentiator from downstream approaches. Last but not least, is our earlier stage translational stage program, the first small molecule program, ANX1502, targeting a host of autoimmune conditions. This is an early translational proof of concept program, which we're excited about. A lot of catalysts over the course of 2026. We anticipate submitting for regulatory approvals as early as January in Europe and later in the year in the U.S. for Guillain-Barré syndrome. For GA, the phase III program will read out in the second half of 2026, really a game changer. The proof of concept study, we will also have data in 2026 on that program. Thanks. That's great. Maybe starting with GBS, walk us through how you're thinking about the peak sales opportunity in the U.S. and EU. How many patients are there annually who develop GBS? We'd love to get a better sense. Yeah, GBS is a sleeper, blockbuster, rare disease drug. I mean, typically rare diseases don't reach that status, but what's unique about GBS is 22,000-25,000 patients between the U.S. and Europe, which is really quite a bit. Importantly, greater than 90% of patients get treated with GBS. This is not a watch-and-wait type of disease. Everyone gets treated. As a result, there's a really significant opportunity. From a pricing perspective, I think our analysts have us somewhere between $100,000 and $150,000 for a course of therapy. That's probably not unreasonable. Could be a little conservative. We think there's uproom, upside on that. We can talk about it as we get into the data and the value proposition of what tanruprubart brings to this disease. We think this is a really meaningful opportunity. The other thing I guess I would say just with regard to peak sales is on the cost side. Cost of goods are less than 3% to treat Guillain-Barré syndrome, which is fantastic for us. It's also a very concentrated sale. Excuse me, when you think about the U.S., less than 200 hospitals see greater than 60% of patients year over year with this disease. That allows you to have a very limited commercial footprint, predominantly Medicare-type folks, as well as some field-based managed cares and just a handful of sales reps. Really an attractive commercial opportunity. Wow. Okay. You have had positive phase III data. You compared this data set to a Western population. To me, you showed superiority over standard care, off-label IVIG in the U.S. What would you say are the most important outcome measures within those data sets that would compel a hospital or a physician to use your drug over off-label? Yeah, it's a really good question. There are a lot of aspects to the data set that we think are really differentiated from what's out there now. IVIG, as you noted, is the standard of care. Everyone gets it, but it's not approved, never been studied in a randomized study. Maybe starting on the safety side first, when you look at Guillain-Barré syndrome, it's a really rapid progressing disease over about a month period of time, and then you spend months, if not years, the remainder of your life trying to recover from that. The safety profile of our drug was similar to placebo in the phase III program, which is huge, a 240-patient program versus the standard of care where you see it's got a black box warning. You see thrombosis in patients somewhere between 10%-15%. We didn't see any of that in our study. From a safety perspective, we're not likely to make patients worse in taking the drug. On the efficacy side, those were we're really excited. Roughly 90% of patients get better at week one with this disease on muscle strength. What that means is by two or three days into the disease, you're able to work remote and sit up, and four or five days into the disease, we see patients getting out of bed. Really, really attractive. What that early impact translates to over a six-month period of time is an improvement in function on all measurements of function, such that by month six, you have a two and a half times likelihood of being back to a state of normal, never been seen before in this disease. This disease can't really just rouse people of their lives. Last but not least, from a healthcare perspective, what really is important is we're getting patients up on their feet and out of the hospital a month sooner than placebo. We're getting them off the ventilator a month sooner versus placebo and out of the ICU a week earlier. These are where the real costs and the real damage to patients are occurring, and we're tackling those in this disease. This is a disease in the U.S. that costs almost $5 billion a year to treat about 8,000 patients. These are million-dollar patients whose lives are completely turned upside down. The disease is completely indiscriminate, and we won on every measure of the disease. We're encouraged about the outlook for this. Wonderful. In the EU, you are submitting to the EMA in January of 2026. All things look good over there. In the U.S., it's been t rickier. A little over a year since you've generated the initial phase III data set. So what exactly has been happening is filing, and it sounds like you want to file in 2026. Is that contingent upon more FDA discussions? Yeah. Good question. Maybe just first to clean up the EU because that's been a much more straightforward kind of approach there. We got our phase III data, our real-world evidence data. We did country-specific meetings across Europe at several countries. That went really, really well. We then had a rapporteur assigned to us from the Netherlands. Poland is the second year. We've had the rapporteur meetings face-to-face, et cetera. All systems go. The agreement we had prior to starting the phase III program with Europe is being recognized that they're deep into the data. These are really substantive discussions, which we're really encouraged by, and we're on pace to file by early January, if not sooner, with that program. The U.S. has been a little bit of a trickier path for us. Same agreement in the U.S. What we've run into with the U.S., this is a program for those who may be less familiar, is this is a placebo-controlled gold standard program. It was deemed unethical to run a placebo-controlled study in the U.S. and Europe because you do have a standard of care IVIG given the devastating nature of the disease. We were encouraged and went over to Southeast Asia, Bangladesh, and the Philippines specifically to run this phase III program with the understanding that we needed to achieve two things. One, substantial evidence on the phase III program. We needed to win against placebo. It had never been a placebo-controlled study done before. Secondly, we needed to demonstrate comparability of the patients in our study to the Western world patient population. We did an additional real-world evidence analysis comparing our patients against IVIG patients from a natural history data set. That is the agreement we had both with, excuse me, with Europe and the U.S. More recently in the U.S., the U.S. has really taken more of a policy approach to programs in the U.S. with kind of an America-first approach that they have been kind of espousing, which is looking to see whether or not they can improve programs in the U.S. for which there have been no U.S. patients studied in the U.S. That was new to us. That caught us off guard because that was not our prior agreement on that. We have had really productive discussions with the FDA on this discussion, on this topic. We do have an upcoming another interaction with them before we can definitively answer the question of what they are looking for. I can tell you what our perspective on it is, is that we probably are going to need to give them some U.S. patient data just to put this topic to rest. Fortunately, we have an open label study that's ongoing in the U.S. and Europe now on the back of the successful phase III study that will allow us to collect PK/PD data from our drug in the U.S. and Europe. We already have that data. We've dosed multiple U.S. and European patients with our drug in multiple diseases. We are very confident of that. We are going to go a step further. We are going to give them efficacy data, at least early efficacy data from these patients as well, which we are really also quite encouraged by. We think it's a very low bar, given that the patients that we treated in Southeast Asia tended to be more severe at baseline from a disease perspective. The preceding infections there, whether it's diarrhea, food poisoning, et cetera, are much more severe in Southeast Asia than they are in the West. They have a higher kind of burden of disease. That's where we won on, which we're really encouraged by. When you look at the subset of the patients in that study, about 25% of those patients who had a milder form of GBS, similar to the U.S. and Europe, we do even better. We're really encouraged by that. We're going to offer up both PK/PD and efficacy data, and we'll get that sorted. We very much intend to file with the package that was agreed to prior to initiating the program and giving them some additional data here. Very helpful. To be crystal clear of your recent interactions with the FDA, it's not like the FDA had any issues with the IGOS or the real-world evidence comparison. Really good question. More like a politics. Yeah. We've gotten no substantive comments on any concerns with regard to our phase III data or the real-world evidence analysis. This America-first concept is one we're feeling like we're going to need to address. We don't know that definitively, but we're planning for that, just given that there's been some maturations in the discussions. Understood. You mentioned you will have another interaction. When is that? It'll be in the new year. Yeah. We were looking to have interaction this fall. It ended up being just kind of communications on written documents, given once the government shut down, the government's now open again, thankfully. That slowed everything down. Now things are moving again, so we anticipate having a discussion with them. We're going to go forward with our plan on this with them. Got it. Also, to be crystal clear, it's not like they're requiring you at this juncture to do this open-label, 30-patient study. You're doing this proactively, it sounds. Yeah, we're doing it proactively for two reasons. One, in Europe, you need to meet this pediatric requirement that you have either studied pediatrics in a prior study or you have an open study for which pediatrics can be enrolled. This study satisfied that for Europe, as well as allowing physicians in the U.S. and Europe to get hands-on experience with this drug in GBS, as I said, they have it in other diseases, but not in GBS. The FDA has never required this study as of yet, but thankfully we have it going, and that will allow us to provide data. The natural question then would be, when could we get 30 patients' worth of data in this board study? Are you sure if 30 patients are enough? Yeah, it's a great question. We've not had a specific discussion on this topic on number of patients. I can tell you our perspective is we don't need 30 patients. What you're looking for is consistency in your data in the West with what you've seen in Southeast Asia. Given the real consistency of the data over there, where 90% of patients got better, we anticipate if we treat 10 patients, we should see eight or nine patients get better, right? We feel the same way with regard to our PK/PD, et cetera. We're not thinking it's that large, but again, we're not the decision makers, and we'll need to have that discussion with them on that. Okay. Is it your base case that my understanding is this FORWARD study, it does go out to 26 weeks, sorry, 6 months? Would you wait to generate all the data in 30 patients? No, not at all. No, what we would be looking for, either it's week one data, because that's where you'll have your PK/PD. The thing about week one in Guillain-Barré syndrome, that is the most prognostic time point for how patients are going to fare out to six months, 12 months, the remainder of their lives. You have to arrest the disease early where you're having damage to the neuromuscular junction and the neurons, et cetera. If you don't do that, I mean, your recovery is just a whole different ball game, right? Week one is really important, and we will look at week four as well. We anticipate cuts at that time point, and we will probably make that data available to the market as well in cohorts. Whether it's 5 patients or 10 patients or something, we want to make this, we want to have a very open, transparent discussion on this disease. I mean, the thing about this disease is no one has studied this in 40 years, full stop, and these patients are suffering from it, and we know it full. We want to be really transparent. We ran gold standard placebo-controlled studies and get the data out to folks. You started this FORWARD study, one last question, back in around May. How's enrollment going out of the 30? Yeah, great question. So number of sites up, et cetera. We have not given an update on number of patients enrolled. Again, we'll do it in cohorts. It's less than five, so I will say that. It's completely episodic. Now, the good news about this is we are going into the high season for Guillain-Barré syndrome. You go into the winter months where flues and other things pick up is really where you see an increase. Look, we can get 5, 10 patients tomorrow. I mean, unfortunately, or fortunately, however you look at it, right? Yeah, understood. So 5 right now, but you expect a pickup. Yeah. I'm saying we haven't gotten 5 yet, but we could get 5. Yeah. Understood. Okay. In the EMA, that's going on well, easier, it seems like, and filing January 2026. It could be approved early 2027 at the latest. Is it your intention to market in the ex-US regions? Yeah, no, not, no, we're not. We're just not experts from a commercial perspective. We've got a research engine here and a machine behind this platform. It's what we do well is the R&D. We're going to pick up commercial, but in the U.S., ex-U.S., we're having really pronounced discussions for a commercial ex-U.S. partnership, which is actually going well. Multiple players around the hoop on that. We anticipate that'll get done, yeah, which is important. Great. Thanks. Shifting gears then to GA, phase III completed enrollment, if my memory is correct, maybe July? Yes, correct. Okay. So data could actually be Q3 rather than Q4. Yeah. Okay. We'll give an update on that. I'm not answering the question. We will give an update there, but we love this study. I mean, this program enrolled ahead of schedule. It's 650 patients enrolled almost two months ahead of schedule, over 30 sites enrolled. It really jumped off the shelf. Really liked the distribution of patients in the U.S. and in Europe on this program with all of the key kind of retina centers in both countries. To make a bigger picture, why do you think your GA program is differentiated from, let's just say, Apellis, Iveric? Yeah, it's a differentiated program all around. As I said, the preamble here is we're stopping this inflammatory process right at the source. The source of geographic atrophy, something that I think is underreported and not talked about enough, is this is a neurodegenerative disease. Full stop, right? A neurodegenerative disease by definition means you're losing functioning neurons in your brain or in your eye, which prevent you from being able to see. C1q localizes on photoreceptor cells, the neurons in your eye that are responsible for visual acuity and geographic atrophy. We're stopping this inflammatory cascade that's causing their removal and the loss of vision. As a result, where we're differentiated from the downstream approaches of Apellis and Astellas is that we are stopping this cascade and we're seeing significant functional vision, whether it's best corrected visual acuity, which is 50% of your vision loss at 15 letters, or at low luminance visual acuity in low light conditions among a host of other measurements. We anticipate a data set that will be highly differentiated, both on the function side, on the vision side, but also on the structure side. I mean, for years, people have focused on the loss of RPE cells and lesion growth. RPE cells are a lagging indicator of the disease. You lose RPE cells once you've already lost your photoreceptors in vision. Protecting RPE cells does not relate to vision. That is why you're seeing the approved drugs out with 3, 4 years' worth of data protecting RPE cells, but no protection on vision. You've already lost your neurons. The horse is out of the barn. We're looking at RPE cells in our study, but as an exploratory endpoint. It's noteworthy that neither regulatory bodies in the U.S. or in Europe even required us to study those. This is a wholesale kind of shift in folks' understanding of what actually is driving geographic atrophy and our mechanism, which is the foundation of our company and what we were founded on. This is a Stanford University discovery, is on all fours in terms of protecting neurons in these neurodegenerative diseases. Great. There have been subtle changes around the phase III program since you first started. I mean, initially you wanted to do a head-to-head study, which was quite compelling to me, but now it's shifted to simply just the sham controls, as I said. Within the sham controls, it sounded like you over-enrolled too. Maybe walk us through. Yeah, yeah, really good question. Historically, to get a label for geographic atrophy in the U.S. in particular, not so in Europe, but you needed two well-controlled phase III studies. We had a construct that we would do one against sham or placebo and one against Syfovre to demonstrate vision against the approved drug. Unfortunately, for Apellis and Syfovre, that drug just really has not demonstrated vision. It's not really a viable challenge to us. Went to the FDA with that discussion on it doesn't really make sense to study this against Syfovre, which they wholeheartedly agreed. They then recommended to us that we run a single phase III protocol and then do two sub-study analyses in the program. We upsized this program by more than 300 patients to make sure each sub-study was well-powered at a phase III construct, which is really, really important for us. As I said, we over-enrolled the study. These are in effect a single protocol with two sub-analyses. They're identical analyses. What I like about it under one protocol is it really reduces or even takes off the table the risk that you're going to have imbalances between two sub-analyses because it's the same patients, you're just doing a statistical cut and splitting them into the sub-analyses. We take a lot of risk out of it. Of course, it's also been much more efficient to run a program like that as well. That's really the genesis of the two analyses. Thanks. Do both need to hit stat-sig? Really good question. Yeah. I mean, first of all, we certainly anticipate they will, and we are playing for that. I guess if you had one win and one that was not stat-sig, I think it would be a question of how close the second study is. You would look at the totality of the evidence. This is a discussion we had with the FDA as well. You would look at the ARCHER study, the phase II program, again, the one that won in the sub-analysis and the second one that did not. In Europe, it is a different story altogether. In Europe, it is just looking for one study. We like that quite a bit. That study is exceedingly well-powered for that. We just need to win on one overall study here in Europe. I see. Okay. Interesting. Can you give us a sense of the powering to the study? The primary endpoint is 15-letter BCVA change versus sham. What kind of percentage drug versus placebo? Yeah. Listen, any win on best corrected visual acuity, 15-letter, is considered a clinically meaningful endpoint. Any stat-sig win on that, and it's powered at the standard kind of phase III rates. We haven't given specific power numbers, but you should assume it's well-powered at that rate because we had an opportunity to do this in concert with the regulators to do that. It's important as best corrected visual acuity and 15-letter loss. I mean, you lose your independence, at least in the U.S., when you score that in consecutive visits, they're turning your driver's license. Again, any significant win on that measurement is deemed clinically relevant and appropriate for approval. There's a lot of precedent for it. Best corrected visual acuity is what's used in wet AMD, DME, et cetera. It is the standard endpoint for visual acuity in these diseases. Got it. Okay. Maybe last couple of minutes, shifting to your oral program. I mean, when we think complements, it's all antibodies. This is pretty unique. You've been working on this oral proof of concept, CAD phase II study going on. Walk us through. Initially, we were expecting to see some data earlier this year. What happened and when do we get the next data? Maybe just kind of paint the picture for everyone. This is, as you said, the first in kind oral drug for a classical complement pathway. All the other programs are antibodies, including our programs, targeting these upstream classical inflammatory components. We started this program roughly seven years ago thereabout with the FODPEP, very much like what you see in the MS space and in the RA space. They all start antibodies, then they go subq. Ultimately, you come forward with an oral, and that's the market winner. We're playing for the win. We're not a "me too" company on any of our diseases. We play for differentiation. We started the program earlier this year. I'm sorry, getting biased. It's been a journey. What we've done is multiple formulations from liquid suspension to film-coated to now enteric-coated, each path along the way really solving for different topics, whether it's tolerability, whether it's food effect, et cetera. We're now kind of late stage in a proof of concept study. What I would say is a challenging patient population, cold agglutinin disease, is challenging because these are elderly patients who are currently stabilized with an antibody. We're asking them to stop their current treatment, go into hemolysis, and then allow us to treat you for a month. That is not a trivial thing for an elderly person. We're doing BID dosing twice a day. That has probably been one of the largest challenges with regard to the conduct of the study. Notwithstanding that, we're seeing a drug that clearly has activity. It's clearly having a role on complement. We're clearly seeing some impact on some of the efficacy biomarkers, but we need more clarity on the data before we release it. We just want to make sure we've got a very clean storyline around this. If it meets our objectives, we're really excited to move it forward. Specifically, the biomarkers you're looking at are. Bilirubin for hemolysis is the key biomarker we're also looking at, LDH, which is also a very key measurement of neuroinflammation in these diseases as well. Okay. Should this meet your go-no-go threshold, which indications are you planning to pursue next? Yeah, well, there are a lot of de-risk indications with this target C1. And so things like myasthenia gravis make a ton of sense, right? I mean, you think about that space, about half of the patients are controlled. All of the patients start off on a cholinase inhibitor, which is an oral. So they've been trained on that. So we like diseases like that. And that's just really kind of in a much more aggressive form of GBS and chronic. I mean, not less aggressive, but more chronic form of Guillain-Barré syndrome, which we know a ton about. We like CIDP and others. And so when we release the data and the go forward, we will certainly, if it's a go forward, we'll certainly identify the indications that we'll move into. Okay. Last question. Definitely data in 2026? Yeah, we will definitely complete the study in 2026. Okay. Very good. Thanks so much for the updates. Thanks, everyone. Thank you all. I appreciate it.