All right, looks like we're ready to get started. I'm Andrew Tsai, Senior Biotech Analyst at Jefferies. Thanks for joining me today, and next up is Annexon. To my right is Doug Love, President and CEO. Welcome, Doug. Thank you. Happy to be here. I guess to help us level set things, some people might not be as familiar with the story. So maybe spend a couple of minutes talking about Annexon, what you're trying to achieve, and how you're different compared to other complement players in the space and milestones. Yeah, happy to do so. Firstly, thanks for having us once again. Always happy to be at Jefferies, so Annexon focused on the classical complement system, and importantly, we're focused on C1q, which is the initiator of the classical complement pathway. What that means is we're providing the most complete protection against complement-derived inflammation and a host of neuroinflammatory diseases. By targeting the top of the pathway, we are providing complete protection against this inflammatory disease process in autoimmune conditions and neurodegenerative conditions in both the eye and the brain. We've been around now for 10 years. The company was founded on discoveries from the late Ben Barres, Chair of Neurobiology at Stanford, and over the 10 years, we've made tremendous progress with this platform, so on the autoimmune space, our most advanced program is Guillain-Barré syndrome, an acute, rare, devastating neuromuscular disease that really causes neuromuscular paralysis overnight. We recently reported a positive Phase III study, which we're really completely thrilled by, and we'll be filing for our first BLA in the first half of next year. Following that, we are in Geographic Atrophy, where we have the only program to receive PRIME designation and the only program to demonstrate significant preservation against the loss of vision in that space. We've also shown protection against photoreceptors, which correlate with visual acuity. And so we're in a large Phase III program that's global, that's ongoing, and it'll read out in the second half of 2026. And then finally, we have the only small molecule program in the complement space, in the classical complement space, ANX1502, targeting a host of autoimmune conditions. We're in a proof of concept study there that'll read out in the first half of next year. The thing I'll just say to take away for everyone is that by targeting complement upstream right where it initiates on diseased tissue, we have the potential to have best-in-class therapies in each of the spaces we're playing in. So GBS, this is the only program that's moving forward for an approval there. And GA is the only program with significant vision preservation. And the small molecule will allow us to really run pretty strongly in a host of neuromuscular and other diseases in the autoimmune space. Fantastic. And just to be clear, you are working on other programs like Huntington's ALS, lupus. So we'll hear more about that. Yes, we're very excited to talk about this. Okay, good, but in the interest of time today, I think let's spend time on your upcoming milestones, namely GBS program as well as the oral program. Starting with GBS, what in the Phase III study efficacy results, because you will do some kind of comparison to natural history, and we're going to expect something later this year, any day now, basically, but anyway, what did you see in the Phase III that leads you to believe this is going to be at least comparable, if not superior, to IVIG? Yeah, really good question, so first thing I'll say is our GBS Phase III program is the first and only placebo-controlled study in GBS in nearly 40 years, so it provides a really comprehensive data set of the strength of our approach in ANX005, the drug candidate that we used, and essentially what we saw in that study is that ANX005 rapidly blocks C1q in the classical complement system, which resulted in improvement on all measures of GBS clinically from week one through week 26. What's that mean? Patients got better sooner on key measurements of function. They were able to walk more quickly. We were able to get them off a ventilator a month sooner. And on the GBS Disability Scale, the approvable endpoint, we were highly statistically significant at week one, week four, week eight, et cetera, so really the totality of the data. That's the Phase III study. As Andrew alluded to, we're also comparing the outcomes from that study to patients who were treated with IVIG out of a natural history data set. That's this IGOS natural history data set. It's a 2000 patient registry. There has never been a placebo-controlled study run with IVIG. So it's a dearth of information on how well does IVIG actually work? What we are doing in comparing ANX005 to IVIG is really answering that question. And there we will release data shortly, as you just alluded to, showing the outcomes on ANX005 versus IVIG at week 1 on things like muscle strength, as well as the approvable endpoint GBS disability score at week 4. And And at week 8, we'll also look at things like ventilation and ability to walk sooner. We're really encouraged by this overall program and the totality of the data to bring something forward to patients who do not have an approved treatment in the States for GBS. Got it. And you know investors not as familiar with the story do get confused sometimes when they look at the Phase III. High dose succeeded, low dose succeeded, high dose did not. But just to be clear, you had thought this through beforehand. Is that right? Absolutely. Yeah. So GBS is an acute monophasic disease, a disease process that lasts roughly two weeks. And the key is to determine when you're inhibiting complement, how long do you want to stop this disease process and then allow complement to come back to be part of the repair process. We saw in our proof of concept study that the lower dose, i.e., shorter inhibition of complement for roughly a week was better than longer inhibition of complement for two or more weeks. But that was a really small study. So we took both doses into the Phase III program. We powered both separately and took alpha separately on both doses in agreement with the regulators so that each is an independent dose. What we saw in the Phase III study is exactly what we saw in the Phase II study, that the shorter inhibition of complement during the really active disease Phase is more optimal than inhibiting past the disease Phase where you need complement to come back and be part of the repair process. So yeah, we were pleased by really validating that treatment window for GBS in this study. Right. And to help investors level set things again, this is an unusual clinical path. The Phase III was in Bangladesh. It was a placebo-controlled study. So I just wanted to make clear that you did receive sign-off from regulators to do a placebo-controlled study, not versus IVIG. And you also got green light to do it in Bangladesh. And you also got green light to do some kind of IGOS comparison there. On all three, absolutely. That is correct. So the reason for that is that GBS is a really devastating, as I said before, acute neuromuscular emergency. You're completely healthy. You get food poisoning. Your immune system kicks on or complement kicks on to clear your body of food poisoning. A month or so later, your immune system kicks on aberrantly, this time attacking peripheral nerves and causing acute neuromuscular damage. Starts in your lower extremities and moves all the way up through your body. One in four patients are going to be in a ventilator within two or three weeks. Completely disruptive. As a result, IVIG is given to all patients, 90% plus of patients in the U.S. But because there has never been a placebo-controlled study with IVIG, it has not gotten approval and it is not deemed to be an appropriate comparator in a clinical study. So in conjunction with the FDA, the determination was made that we needed to run this study in Southeast Asia where IVIG is not readily available. You cannot withhold it in the U.S. because of the severe nature of GBS. So we got sign-off on that, which was really, really important. And you mentioned something else. IGOS comparison. Yes. So the approval to get a label is you need to win on your Phase III study, and then you need to demonstrate that the patients in your study are comparable from Southeast Asia with patients in the Western world, in the U.S. and Europe. To do that, you match patients from our study with patients in this IGOS natural history data set based on key prognostic factors. Typically, these are predominantly prognostic factors of disease severity. So your baseline muscle strength, your baseline scores on GBS disability scale. So we worked out a protocol to do that with the regulators, which has been fully signed off on, and that is the work that we are doing now. We are determining that the patients in our study match patients in the Western world. Really, really important. So the translatability of our outcomes is pretty much the same across the globe. We're going a step further in also comparing the patients in our study who got treated with ANX005 with patients in the IGOS data set who got treated with IVIG. Right. Just the nuance here is FDA, as long as you match it, you can. Matching is the requirement. That's right. The additional information for the marketplace is our comparison against IVIG, which we think is important so that people have an understanding of what we look like versus standard of care. Yeah. A part of what makes me very hopeful is not only the Phase III data, but just, you know, I guess my question is, how does this Phase III data set compare to what you saw initially with the Phase I B data set? Because after the Phase I B, you did get an ODD designation from the EMA. And the EMA explicitly said in the meeting minutes, this is clinically relatively advantageous to IVIG or something like that. Yeah, very well said. Yes, so we've done this exercise that we're doing with the Phase III data set previously with our proof of concept data set, so we had a readout with our proof of concept. We compared the patients in our study with the Western world using the IGOS data set, and we also compared the outcomes in the proof of concept study with patients who were treated with IVIG in the IGOS data set. We submitted that data to the regulators in Europe to make a determination whether we qualify for orphan drug designation. To get orphan drug designation, you need to establish a likelihood of being better than the standard of care, and what Andrew was alluding to is this 10-page single space document from EMA, which we love. They went really deep in assessing this topic that we are indeed likely to be better than IVIG based on our proof of concept data set. Where we're encouraged is our Phase III data is actually better than our Phase II proof of concept data set. So it bodes well for us, but we got to complete the analysis and we'll present that shortly to the marketplace. Okay. And I guess because EU, my understanding IVIG is approved in the EU for you to be approved. Presumably you would have to show superiority in this IGOS data set or not necessarily? It's to be determined. We do need to show that the patients in our study are comparable to the patients in the West. What they'll actually need with regard to IVIG is still a little bit to be determined. IVIG is approved in Europe, but not because they ran clinical studies here. It's just listed on a compendia for I think almost 60 uses for IVIG. And it's really a default and speaks to the severity of GBS as a disease. You got to do something to stop this disease overnight. Right. Okay. And speaking of IGOS, any day now, I guess what are the measures you're looking for? You hinted at it earlier, I think, but just remind us one more time. What exactly is the primary endpoint? How does this? Yeah. It's really important to show an outcome versus IVIG on the clinically relevant measurements for this disease. So we are looking at week one, which is a really important time period for this disease. If you do not arrest this disease in week one, you're in really bad shape. It is the number one prognostic factor for how patients are going to fare with GBS. And so we'll look at week one and particularly muscle strength at week one. Do you have the ability to regain some muscle strength to begin to move? And can we begin to move patients out of the ICU, which is really, really important? We'll also look at week four on the GBS disability scale. This is a very discrete scale. This is the approvable endpoint scale. So are we moving patients off a ventilator? Are we moving patients, giving them the ability to walk, the ability to run, et cetera, more quickly? We'll look at week eight, which is also in our study. We will also look at week 26. How durable are the outcomes with our study versus IVIG? Week 26 is going to probably be a little harder to assess. There's just less IVIG data out there for out to six months. We have a very robust data set, so we will look there as well. And then things like, which are really important to the healthcare system and to patients, days on ventilation. Can we get you off the ventilator sooner so that you can get back to a recovery state? Can we get you back to walking sooner so that you can get walking? Really correlates with getting you out of the hospital. Like if you can't walk, you're still in the hospital. We can get you back on your feet sooner. We know we did that versus placebo very well. We got patients walking a month earlier. We got them off a ventilator a month earlier. And so we'll see what that looks like with regard to IVIG. Makes sense. And for you to establish comparability or superiority, should we be looking at multiple measures? Is it about the totality of the data or are there multiple ways to win? Yeah, absolutely. Really good question. Yeah. So we absolutely will be looking at the totality of data. It's a composite. I mean, these patients are impacted in multiple ways. So we want to see their muscle strength. We want to see them on GBS disability scale. We want to see what they look like from ventilation and from a walking perspective. So we'll look at the totality. But the primary is week four and week eight are the two time points that matter the most from a GBS disability scale. So we'll be looking at that discretely as well. I see. And what can we expect in the top line release? Read out on all those key measurements that I just referred to. Very good. And let's just say in the scenario where it was comparable to IVIG, maybe some investors might ask, why would this be used in the marketplace because IVIG is generic and cheaper? What would you say to that? It's a really good question. Yeah. Well, listen, IVIG, first of all, has never run not only a placebo-controlled study. There are no well-controlled studies. IVIG has not run a study versus a comparator. You can look at the literature. So we really do not know how IVIG works and if it's really effective. One, two, IVIG is dosed over five days. That's really, really important for patients who are in the hospital with this acute neurological emergency. We're dosed over a matter of hours. So we're stopping the disease right away. And if you think about a hospital staff, having to tend to an infusion over five days is not trivial. And then finally, I guess what I would say is that when you look at the safety profile of our drug, it really very much looks like placebo. Really very safe in this study, whereas IVIG has a black box warning. I mean, almost 10%-12% of these patients get thrombosis and other things in GBS with the treatment of IVIG. So not only do we anticipate we'll be comparable or better from an efficacy perspective, we do think we have some meaningful advantages with our drug just in how it's dosed and the safety profile at a point where patients are really vulnerable from this neurological emergency. Understood. And after you do this analysis, hopefully positive, what's the next step in terms of FDA discussions before you file? Yeah, so we're having ongoing discussions with the FDA. We're really pleased by that after the Phase III data. We'll get the data from this real-world evidence. We will go into a pre-BLA meeting early part of next year, and then we will file for BLA in the first half of next year. Great. And I should have asked this from the very beginning, like how big is the GBS market in terms of peak sales potential? Yeah, it's a really sizable market. We think it's frankly has potential blockbuster potential. 7,000 patients a year get GBS. 95% of those patients get treated with IVIG because when you show up to the hospital, you do not know if in a day or two you're going to be on a ventilator. So everyone has to get treated. Another 15,000 patients every year in the U.S. get GBS, and it's the same circumstance. They show up to the hospital, everyone gets treated. So this is a really active market opportunity, and because there are no approved drugs, there's no share of voice out there. No one is promoting to the hospitals, to the patients, et cetera. So we really get to come in and tell a story about the disease and a treatment for the disease. So we think it's a real opportunity. Okay. So then let's move on to your old program because we do have some initial Phase IIa data and CAD coming up in Q1. Correct. High level, I guess maybe it's obvious, but why is this potentially a game changer? Yeah. No, listen, we like it. So this is an ANX1502. As I said before, this is the first small molecule program in the classical pathway. And importantly, we're targeting a host of really devastating autoimmune conditions, many of which are neuromuscular in kind, like Myasthenia Gravis, CIDP, et cetera. These patients are suffering from anemia. They're suffering from an inability to move and maintain activities of daily living. They're currently being treated with IVs that are infused every other week. These folks have to plan their lives around going to get an IV so that, I mean, it just, they're completely wiped out afterwards. Being able to offer them the ability or the convenience of an oral therapy that is stopping complement high up in the classical cascade. So we think from an efficacy perspective, really strong opportunity there. But the oral gives them an opportunity to take this in the comfort of their homes, and you look at many of these diseases that we like, like Myasthenia Gravis, where C1s inhibitors are used. These are small molecules, reasonably effective. Transitioning to a small molecule that really attacks the disease is really important, so we like it for the ability to go into proven indications that have already been clinically de-risked with IVs with an oral and really play strongly in that market, and because it's an oral, it allows us to study other diseases that are difficult to do with IV, and we have quite a list of those, which we're excited to get after. Great. And walk us through just briefly what you've done in the Phase I to be prepared for Phase II? Yeah. First oral in this classical complement space. It's not trivial. We can't take it lightly. We've been working on this program for eight years. So we're not dabbling in this space. We ran a healthy volunteer study with liquid suspension first to just demonstrate that the drug was safe and well tolerated, A, and B, that we could get the appropriate drug levels and PK out of that study. We then transitioned to a film-coated tablet, which also demonstrated itself well tolerated, appropriate drug levels, PK, et cetera. We did see a hint of tolerability in that, both in the liquid suspension and the film-coated tablet, where patients were having a bit of nausea, emesis. Nothing that was rate limiting to stop the program and to continue to move it forward. But in the background, we began to work up an enteric-coated approach to this, which we recently completed a healthy volunteer study. And we're really pleased to show it demonstrated, again, really good PK levels, really good drug levels, but importantly, it really tackled any tolerability issues. And so it really minimized the tolerability issues. And so that's the drug candidate that we've moved forward into a proof of concept study to demonstrate really the pharmacodynamics of ANX1502 from a PD perspective. Maybe talk a little bit more about that Phase IIa study in terms of patient numbers, duration, and so forth. Yeah. So we're doing this in Cold Agglutinin Disease, a rare, really, really rare autoimmune condition, hemolytic condition. What we like about it is the role of C1s in the classical complement cascade has been very well validated. There's approved drug there for that. We also have demonstrated it with our antibody ANX005. So we know a great deal about how this drug works. One, two, it's a super objective endpoints in this study. So we're really just looking to show impact on hemolysis to establish pharmacodynamic effects with our small molecule, which has never been done with an oral in the classical pathway. So not a trivial step for us on that. We're really looking to normalize bilirubin, which is a key measurement of hemolysis in this disease, typically changes in about a week, very short period of time, as well as impact on downstream complement markers, C4, C4d ratio, really showing that we're stopping the activation of the cascade right at the start, another very key pharmacodynamic measurement. We're doing that in a very small number of study patients, three to five. The reason we're doing that is CAD is a very small indication. We don't see it necessarily as an attractive commercial indication, but we like it in establishing our drug candidate, getting the data from that, and then moving forward in a host of neuromuscular and other diseases with this study. I see. And sorry if you said it early, how long is this study? Oh, four-week study. Four weeks. We'll have the data pretty quickly. I see. And you know when I looked into the Enjaymo paper, Phase I, they did in 10 patients. Yeah, bilirubin did change meaningfully. How about hemoglobin, I guess? Yeah, hemoglobin bounces a bit. So when we look at the, including our study and other studies, what you see in hemoglobin is about two-thirds of patients have an impact on hemoglobin. And typically that's at month three. In a four-week period of time, there's not a real expectation that you would move hemoglobin. We will look at it. But what's important is that, as you said, bilirubin moves quickly and it is the surrogate to hemoglobin. And it moves in a week and all patients should move. And we should see a normalization of bilirubin. Okay. Very good. We'll wait for that data set, and I guess in the last few minutes, GA, Phase III underway. Pretty fascinating to me to follow this because you have the only prime designation. I think Apellis got rejected three times, and then Iveric just withdrew their MAA, so maybe talk about that. Yeah. I mean, I think you guys are familiar with Geographic Atrophy. This is a disease where patients in a very vulnerable state in their lives, typically in their late 70s and 80s, are losing vision. What's that mean? They're losing their independence, their ability to see their loved ones, the ability to cook their own meals, their ability to drive their cars. I mean, it is a really significant thing because if you don't have the proper cure at home, that means you're moving out of your home into a care facility as you have this disease. I don't think people talk about the disease enough. It's really, really relevant because the drugs that are approved here are approved on a biomarker of lesion growth. Unfortunately, this biomarker does not at all associate with visual acuity. So you can have an impact on this biomarker. You can be approved for it, at least in the United States, but you're not preserving that patient's vision. So all of the untoward things associated with the disease are still happening to these patients, and it's why these drugs, unfortunately, have not been approved in Europe. Europe is looking for functional benefit. That's what we delivered in our 270-patient proof of concept study, sham control, significant preservation against vision loss in both normal light conditions and low light conditions. So two separate assessments. We also show preservation of the key structural elements in the eye associated with visual acuity. That is preservation of photoreceptor cells or neurons in the eye that are responsible for receiving light and so that you can maintain vision. So we have the function and the structure that really complete the story. We're now in a large Phase III study, 630 plus patients that's being run globally in the U.S. and Europe and other countries. Really excited about this program, really excited by the KOL and physician buy-in as well as the patient populations. We're really just very focused on bringing a therapy to patients that's going to change their lives from a very vulnerable state in their lives. Right. And one Phase III you're going, there was an original plan to do a head-to-head versus Apellis, but now that they've been rejected in the EU, cases of retinitis, vasculitis, does it make sense to do one? We're assessing it. I mean, as you said, when we started this program a year ago, we were going to tackle the 500-pound gorilla, the king of the mountain, if you will. There's some challenges with that program now. I don't know if we get the benefit in going after them at this stage, but we're assessing it. We'll have discussions with the regulators. And maybe we just stand still on our program alone and move that forward, but to be determined. Okay, and then just to be crystal clear, Apellis has shown retinitis, vasculitis. I can't tell if Izervay has, but you have not, just to be clear. We have not. No, I mean, one of the things that's very unique about our drug candidate from the other programs which are in this space is our drug is completely non-pegylated. So this is a very natural antibody that's a Fab administered into the eye. In fact, it was built on the backbone of Lucentis intentionally. So we've stayed away from pegylation, which may be a contributor to vasculitis. Not to say we'll never see it, we don't know, but we have not seen it in any of our programs thus far. Okay. Lots of things to talk about, but definitely some.