My name is Leon Wang, one of Tazeen Ahmad's associate. It is my pleasure to introduce you all to Douglas Love, CEO of Annexon. Doug, pleasure to be here. Thanks for having us. We're really happy to be here this morning. Great, great. For those who may not be as familiar with the Annexon story, can you give us an overview of the technology? What's in your pipeline? Yeah, absolutely. Yeah, Annexon's focused on complement, and specifically the classical pathway, one of the three components of the complement system. What our thesis is that by blocking C1q in the classical pathway, we're providing more complete protection against aberrant complement activity. In a nutshell, in indications or diseases where complement is a key driver of the disease, we're stopping that process right at the start and with the hypothesis that we'll have increased efficacy. We're doing it in a selective way by only blocking the classical pathway, allowing the lectin and alternative pathways to remain intact. We think from a safety perspective, they may be fruitful as well over time. We've got a couple of data sets thus far that are tending to prove this out, validating the thesis. One in our GBS program where we showed rapid improvement in this very aggressive antibody-mediated autoimmune disease. The second in Huntington's disease, a historically difficult to treat indication whereby we showed, again, rapid improvement in disability, and function in that disease as early as week six. We've pulled together a portfolio of programs that target three therapeutic areas, autoimmune, neurodegeneration of the brain, or neurodegeneration in the eye. We currently have eight studies ongoing. We anticipate readouts over the next 18 months. We're quite excited about each of these opportunities as we sit here today. Excellent. Thank you for the overview. I think what a lot of investors have been curious about is really the anticipated readout, ANX005, that's gonna be in Huntington's. Can you set overview of what you plan to show and perhaps set some expectations for, you know, what might be the target to hit for this program and what could we potentially see in terms of safety and efficacy? Yeah, really good question. As you know, Huntington's disease, a classic slower progressing CNS neurodegenerative disease that's historically been very difficult to treat. Our approach is by targeting C1q in the classical pathway, is to preserve functioning synapses, and as a result, provide improvement in disability in this indication. We released initial data in January of this year, interim look, which showed our ability to stabilize against progression of this disease in the full patient cohort. That's a really important finding. To get a label in Huntington's disease, you really need to only slow the rate of progression of the disease. We were encouraged by seeing a stabilization in the full patient cohort, as well as improvement in function in more than half of the patients. Importantly, those patients who entered the study with excess classical complement activity, 75% of them showed improvement. Really aligned specifically with our mechanism of action, which is blocking this aberrant complement activity right at the start. That's what we showed in the interim. What we will show in the full data set later this quarter is a fuller set of data on the on-treatment period, which is a 24-week treatment period. Then there's an off-treatment period, another three months, so out to 36 months. We will provide data on the off-treatment period as well, on the efficacy measures and the other measurements in the study. What I anticipate producing again later this quarter is data on our drug candidate, ANX005. It's a really potent inhibitor of the classical pathway. We've already demonstrated full target engagement both in the periphery and across the blood-brain barrier. We'll look and see how long that inhibition of complement occurs in the off-treatment period. That'll be an important data set. On the efficacy side, we will look to see the durability of effect, this durability of stabilization or improvement in patients after we've withdrawn the drug. We think part of that will be tied to the length of suppression of complement in the off-treatment period, i.e., how long is C1q still suppressed after we've stopped treating? We'll learn more about our drug as it relates to that. Of course, the actual clinical readouts out there as well. We'll be looking at safety in the full cohort. Our initial safety update in January was a subset of the population. Gotcha. Huntington has been a big focus, you know. Your method of targeting Huntington's is very interesting. In terms of potential combinations with other drugs that's currently out- Great question. Well, not out in the market, but you know, in pipeline, right? Mm-hmm. Do you see this as a, you know, this is the ANX005 or the Roche product or, you know, depending on what they do with? Right. You know, could this be like something that could maybe work synergistically based on the biologic rationale? Really good question. Yeah, we think both is the short answer. As a standalone, protecting functioning synapses, we think can be really important in improving disability. In fact, the loss of synapses has the highest correlation with cognitive decline and motor function of any other measurement you can look at or activity you can look at. As a standalone, we quite like it. Importantly, our approach is not targeting what may be the initial assault of the disease. Whether it's mutant huntingtin lowering type activity which may be driving it, we can work in synergy with that. Whatever the initial assault of the disease may be, what we do know is that assault is triggering complement and then causing the removal of synapses via the classical pathway. That's going to be occurring even if you target the initial assault. We think we can put the two together, I guess, is the short way I would say that. Great. Appreciate the insight. Why don't we move on? I mean, you have a lot of different indications that you're going after, and some of these indications, you know, have controversy. Let's talk about ALS, right? What should we kind of you know, if you want to set it up for us in terms of what should we expect later this year? I have some follow-ups on specifically. Yeah. No, listen, we love ALS program. Just one point of clarification, so we've guided to ALS data in 2023. Yeah. Not this year. Yeah. One of the things we like about ALS is it's obviously a very aggressive neurodegenerative disease that involves both the periphery and the CNS. We have studied similar indications that are nice read-throughs into what we hope to see in the ALS indication. One would be GBS, where it's an acute disease that causes damage to peripheral nerves. Damage in and around the neuromuscular junction and peripheral nerves, very similar to what you see in ALS on the periphery side. Of course, in the Huntington's disease, a central disease where we're preserving functioning synapses, which also is lost in ALS. We look at GBS as a very aggressive disease. Huntington's is a slower progressing disease. ALS is right in the center. We've produced data sets that showed improvement both on motor function as well as cognition. It gives us a reason to be encouraged with regard to ALS. Mm-hmm. I think the more recent controversy we've seen with ALS is just how do you assess the endpoint there, the ALS FRS? Yeah. You know, those are discussions that need to be had with regard to the regulator, but that's different in kind than with regard to kind of your mechanistic approach, if you will. Gotcha. In terms of expectations on the readout, you guys guided to 2023. What do you think that you would be kind of like a home run for, what you might show on the readout and, you know, is this potentially first half 2023, second half? Yes. Great question. We have not. Yeah. honed in on the specific timeframe of 2023, but we will update as we get closer to that. We know that it's a rapid progressing disease, so a steep decline. What we also know and from other programs and interactions with regulators, that if you are slowing that rate of progression somewhere between 10%-20% Mm-hmm. Statistically, you're meaningfully improving patients' lives, and you're likely to get a label. Anything in that ballpark is a real win. If we stabilize the disease like we saw in HD, well, that's more than a home run. So we'll have to wait and see what we see in the data set. Historically, the aim in treating ALS is to slow the rate of progression. Great. Amazing. Why don't we move on to GBS, another one of clinical trials that I think last time you mentioned there's some progress with enrollment. However, it has taken a significant amount of time to get patients. Can you provide any updates on the current enrollment? What is the rate limiting factor here? Yeah. GBS is very much on track in the way we guide it from the outset of the program. I mean, maybe just to take a step back. GBS is an acute antibody-mediated disease. It causes the number one cause of acute neuromuscular paralysis in the world. 5% of patients in the U.S. still die from it. 25% still go on a ventilator. Very gnarly disease. Because of its acute nature, you have to wait till the event occurs. It happens in about 6,000 patients in the U.S., and another 6,000 in Europe on an annual basis. We've been very much on track, if not a bit ahead in the way we've been conducting the study. We had no slowdowns as it relates to COVID. We are conducting the study in Southeast Asia, where there's a high prevalence for the disease, and so remain on track for 2023. We're excited about the program just based on what we demonstrated in our proof of concept study. Gotcha. Well, actually, any conversations with the regulators about potential path forward? Is this going to be the registrational trial? That's a great question. Yeah. Certainly the discussion that we have been having with the regulators, and we've purposely titled this a phase 2/3 study. Mm-hmm. The aim is to have a single study pivotal. We've designed it as a pivotal study. 180 patients, well-powered, fully randomized. Importantly, you know, we have set it up where we have enriched the program based on prognostic factors. We've, you know, stratified patients based on their MRC levels, time to treatment onset from symptoms, et cetera. The discussion with the regulators are they'll need to see the data. Mm-hmm. To see if it's a single study approval is the long and short of it. We've designed it with that in mind and we'll wait and see some data and get in front of them with that. Gotcha. Okay. That's very helpful. Why don't we move on to ANX007. As you know, there's a lot of activity, especially recently in the potential complement within geographic atrophy. Now, there's a lot of players that's currently going after GA in different paths of the complement. You guys are going after it in C1q, right? Can you talk about what potential differentiation that 007 could provide and what gives you know, the confidence that within complement, you know, might not necessarily be C3/C 5, but potentially some cases. Really good question. We really like the geographic atrophy indication. First thing I'll say is that we are encouraged by the role of complement in geographic atrophy as validated candidly by the C3 approach downstream. And we respect that data quite a bit, and we think it's providing some benefit to patients. That being said, we think there's an opportunity to improve upon the benefit that's been demonstrated thus far. Again, it gets back to our underlying thesis for our approach, which is to the extent that complement is driving the disease process, by stopping this complement activity right at the start, you're providing more complete protection against this aberrant complement activity, you see a rapid, meaningful improvement. We think we have an opportunity to improve upon that. Maybe to click into that a bit deeper. When you look at C1q, it actually sits on and anchors the disease tissue in geographic atrophy. C1q is localized on both sides of photoreceptors in geographic atrophy as well as on drusen, the hotspot for the disease. It is there where complement is actually anchored and then activated and amplified thereafter. By stopping it right at the start, we think we have the potential for really unique outcomes. We've seen that in another neurodegenerative disease, Huntington's disease of the brain. This is, you know, neurodegeneration of the eye, and they're certainly related in some regard to the extent the eye and the brain are interconnected. Yeah. We're encouraged by that. In terms of differentiation, one would be, we would hope to be on the efficacy front. ANX007 is another. It's a really strong drug candidate. It's been in over 200 patients thus far, been very well tolerated, really complete inhibition of C1q and the entire classical pathway down through C3 and C5, which I think is a very important point. We're not just blocking upstream complement, we're blocking downstream complement as well with ANX007. We've also demonstrated in a placebo-controlled study in patients our ability to dose the drug monthly and every other month is our belief. Mm-hmm. We've taken both doses into the study. We could potentially differentiate on every other month dosing, so less frequent dosing as well. The last thing I will say is, and I mentioned this earlier, we are only blocking the classical pathway, and we are allowing the lectin alternative pathways to remain intact to perform their natural immune function. Over time, in this chronic disease, in an aging population, that may result in an enhanced efficacy profile as well. We'll have to wait and see the data, but we're certainly hopeful that could be the case based on the biology of the approach. Yeah. Well, going into a little deeper on that, right? One of the questions that we have is not necessarily specific to Annexon, but just in general. You have complement, but also where is complement best in treating the disease in terms of the progression of disease? You have folks with extrafoveal, you have folks with foveal, probably broad foveal scarring. That's right. If you know, you have people that's approaching even clinical trials and there's various different type of disease subset within geographic atrophy. When you look at C1q, is this something that you know, could potentially work better or you know, based on your thesis earlier in the disease, in the middle, or perhaps this is in the back end coming in to save somebody that already has lost a lot of photoreceptors? Right. I just want to thank that. I think, you know, the general thinking is in all neurodegenerative diseases of the brain or the eye, treating earlier is better. Mm-hmm. Right? Before you lose too much neurons because they do not regenerate. Partly synapses can come back and they can, you know, plump back up, et cetera. We generally think it's better to treat earlier. As you think about foveal, non-foveal or aggressive and non-aggressive disease, we powered our study to look at both. With the thesis being that if complement's a key driver, we're providing the most complete protection against this complement activity by stopping it at the start. We've powered this study where we can win in all comers. That's both foveal and non-foveal, and enrolled almost half of the patients who are non-foveal, so we can win just in that aggressive population as well. We've given ourselves multiple ways to show efficacy in this study. Gotcha. That's helpful. In terms of the market size, let's say, you know, roll forward, you have your products on the market, but so is Apellis, so is Iveric Bio, potentially NGM. Do you see, do you see yourself as needing to capture market share from other folks who may have gone on to the market before you? Or do you think the overall market size and opportunity just within complement is big enough that you potentially have three, potentially four different players in it? Yeah. I mean, certainly it's a big enough market to have multiple players. I think, you know, when you look at GA, to me, the analog is wet AMD, where you have multiple players. Mm-hmm. We think it certainly can house multiple strong players in this market. Ultimately, the need to capture market share or displace others will depend upon profiles of the drugs, right? Sure. No approved therapies yet, right? Understanding the profile of the competition or potential competition in our drug ultimately will be the final arbiter on all that. Gotcha. With the number of updates with other folks in complement this year, which one do you think will have the greatest read-through to your product? Well, it's the complement ones, certainly. Right? It's the complement approaches that, again, with Apellis, and they continue to produce data out over periods of time, which is encouraging from my perspective. Iveric Bio in their C5 approach will be important. Again, the complement approaches provide the validation for our approach, and we're just moving upstream and inhibiting upstream and downstream versus just downstream. Gotcha. Okay. Why don't we move on to wAIHA? Can you just give us a quick overview? When is the next update? What should we expect? Yeah. Yeah. It's a program we really quite like for many reasons. wAIHA, warm autoimmune hemolytic anemia, is an antibody-mediated disease where antibodies attack red blood cells and cause anemia. Happens in about 45,000 patients in the U.S. We are taking a precision medicine approach in this particular indication. There's a fair amount of heterogeneity in the patient population on what is the underlying primary driver of each patient's disease. We see approaches like Syk inhibitors and FcRn, which work, it appears, in a subset of the patient population. But what we've done is we've characterized the role of complement in this disease to understand these patients who do not appear to be responding to other approaches. You know, these other approaches impact, at best, roughly 50% of the marketplace. Mm-hmm. We see these other patients. We've characterized the role of complement, and where we have identified patients who have excess or aberrant complement activity, classical pathway activity, those are the only ones we're targeting for our study. It's a very targeted precision medicine approach that we think should have a higher PTS. We have a Phase 2 study, which is doing the screening process for all patients to identify their complement signature. We've profiled more than 50 patients there now. Mm-hmm. Of those who meet the criteria, those are the ones who are being enrolled into the Phase 2 study that is ongoing. Again, a very enriched program. We anticipate initial data latter part of this year, where we'll be looking to show impact on hemolysis and hemoglobin levels in that study. One of the questions that we are getting in terms of within just, WAIHA for the disease is just the market size and opportunity, especially you're also targeting complement within- Right. Within the disease state. What are your thoughts about one, the potential market size, how much you can potentially penetrate within that market? Yeah, it's a great question. We know, or the literature has told us, and then we've confirmed it with our non-interventional study, that about 25% of this population has complement as a key driver of their disease activity. Mm-hmm. You know, with 45,000 patients as the overall U.S. market, that's a sizable portion of patients to treat on a chronic therapy that are otherwise uncontrolled. We also have the potential, over time, we believe, to go further than that. When you look at wAIHA, there's a gradation of what's driving it. Is it Fc receptor-type activity, or is it complement? And patients are on a continuum. We are targeting patients where complement is clearly the key driver, but there is a mix of patients who have a mix, where the Fc receptor activity is driving it as well as complement. We think we can potentially expand into that space as well, which would be roughly 50% of the overall population. We're comfortable with 25%, and then there's a path forward to maybe increase that. This is 50% of the total or this is. Of the total. -additional? Of the total. 50% of the total. Yeah, that's correct. What has been kind of the screen out rates so far that you've conducted? It's about 25%. 25%. That's what we've confirmed, yeah. You know, we've pulled again, we've screened, profiled more than 50 patients. Again, if you look at the literature, it's very consistent with regard to that. About 25% of them are who meet this primary complement-driven disease. Gotcha. That's very helpful. In terms of how, obviously, COVID has impacted everybody, also war in Ukraine, has these kind of global macro factors affected Annexon in any way? More specifically, do you anticipate any slowdowns in the clinical trial readouts, or is there a potential, like do you have sites in Ukraine that's potentially enrolling? Yeah. Good question. No, no sites in Ukraine, and we've really been able to manage COVID quite well. Really pleased with the team's effort and engagement. We've hired a team of really seasoned, strong drug developers who are playing with their hearts and minds, like they really are into the science. What we've seen across these multiple studies, and we've got a lot going, right? Mm-hmm. We're not faint of heart in prosecuting this platform. We've been able to, for example, enroll the GA study ahead of schedule. Almost two quarters, we crushed it. GBS on track, if not a little bit ahead of schedule. wAIHA, we will have data later this year. Lupus nephritis later this year. ALS, we're continuing to work through. HD, we actually brought in earlier. We'll, you know, report final data later this quarter. We've been able to navigate that. Including healthy volunteer studies, which we're doing in Europe as well with our next-generation drug candidates. Mm-hmm. So. Gotcha. In terms of other macro factors, we're in a very turbulent biotech market. I'll say. Yeah. When an investor looks at your company, right? They see you are targeting a lot of different indications. Correct. A lot of them would need a lot more capital to potentially drive it to approval. How are you thinking about your portfolio from a portfolio strategy perspective? Any insights or colors that can help investor understand like what would potentially the next 24-36 months potentially look like? Yeah, that's a good question. How are we capitalized to do all of this? Yeah. How are we gonna do this, right? No, it makes sense. The first thing I will say is that we will capitalize to cover our eight current studies. We have cash runway into 2024. That's encouraging. The other thing I will say is that we have multiple catalysts between now and then in which to read out and to potentially raise as early as, you know, maybe the second part of this year, if not sooner, as we begin to roll out data, and then into 2023 with additional studies. That's one strategy is to continue to look for opportunities where it makes sense to bring additional cash in. We of course have to balance that with the overall dilution and things like that. We're assessing all of that kind of real time. There's certainly the way we've set up the cadence of catalyst and opportunity to do that. We also have had a fair amount of inbound interest with regard to the neuro program in particular, because pharma has really dove into the HD data, I think differently than maybe what we've seen on the equity side. Mm-hmm. Stands to reason, you know, that, you know, larger companies would be diving into the neuro space and neurodegeneration in a different way. We've been really pleased at what's circled around the table. If that is an accretive opportunity for us where we could perhaps grow the pie or some such thing, we're open to that. We're certainly having the discussions and we'll see, but that's a potential for, you know, less dilutive dollars sooner, an opportunity to bring on additional capabilities, et cetera, to continue to expand in neuro, or maybe we focus a bit more on the autoimmune and ophthalmology side. We will see how that plays out. The third thing is maybe just, you know, natural attrition to the portfolio. Mm-hmm. Our thesis has been that protecting complement right at the front is going to be very effective in multiple therapeutic areas and multiple indications. You think about what we're doing, we're studying all of these in parallel and leveraging learnings where we're targeting complement in the kidney, in the blood, the peripheral nerve, the neuromuscular junction, in the brain, and in the eye. We think it works in all of those based on our preclinical work, but that may not translate into the clinic, and so that'll help inform what we need going forward as well. We're really rigorous about assessing data and following the data. We're not gonna push forward if the data doesn't support it, but if it does, we'll look for ways to figure out how to do that. All right. Excellent. One last question before we wrap up. For your neuro programs, is this something you're looking for as a potential out license, or do you wanna do a partnership type of a deal, maybe regional? Just kind of thinking out loud. Good question. Yeah. It would certainly at a minimum be a partnership, not just a complete out license. We know it's a first in kind approach. Mm. Our scientific co-founder, Ben Barres, discovered it. We've been working these models from early preclinical now into the clinic. We know a ton about it, and we know a ton about the drug candidate. At a minimum, it would be some type of profit sharing, you know, partnership. Regional may be a very smart play to do this as well. Assessing all of that real time. Gotcha. Okay. Well, that's it. Doug, thank you for coming over and hope you enjoy the rest of the conference. Yeah. Thank you so much. Thanks for having us. We appreciate it. Definitely.