All righty, folks, we're gonna get started. Give these guys an opportunity to grab a seat and hit the doors. All righty, folks. Well, listen, good afternoon, everyone, and thank you for joining us today. I'm Doug Love, President and CEO of Annexon Biosciences. And we're excited, delighted that you've joined us this afternoon for our Investor Day focused on vonoprument for the treatment of geographic atrophy or GA. Here, we'll discuss its robust scientific and clinical underpinnings that support the vision-sparing data that we've seen in our phase II study, and really gives us a great deal of encouragement for our phase III program. We'll be making forward-looking statements, of course, and we direct you to our legal disclosures here and on file. Over the course of today's program, you'll hear from members of the Annexon management team, as well as leading experts in geographic atrophy. We thank our experts for coming out today. Dr. Nora Lad, Vice Chair of Ophthalmology Clinical Research at Duke, and Dr. Charles Wykoff, retinal specialist and Chair of Clinical Trials for the Retina Consultants of America. Following a brief company overview, I'll turn the baton over to Dr. Lloyd Clark, a retina specialist who also serves as SVP of Ophthalmology and Strategy and Innovation for Annexon. Lloyd will then pass it over to a very important talk by Dr. Lad, who will provide a deep dive into GA's mechanism of action, and importantly, the role of C1q in the classical pathway that drives vision loss in this disease. Dr. Wykoff will then come up to review the outcomes of blocking C1q inflammation from the phase II ARCHER trial, including the important structural and functional benefits that are demonstrated in that study. Finally, Jamie Dananberg, our Chief Medical Officer, will provide a review of the ARCHER II phase III pivotal program and provide a brief update on the status of that program as well. We'll then close with a roundtable discussion with our experts, and then ask you to join us for a reception. An action-packed agenda, and we're just gonna dive right into this. Before diving into the heart of the program, I'd like to quickly provide a little bit of background on Annexon and how we got to here today. Annexon was founded with the bold mission to create an entirely new class of targeted immunotherapies to treat neuroinflammation by stopping harmful C1q-driven inflammation, where it starts on diseases in the compartments of the body, the brain, and the eye. Our mission was and is to deliver meaningful functional benefit for patients living with a host of devastating neuroinflammatory diseases. Importantly, all of the diseases in which we are pursuing have significant unmet need and afford us the opportunity to help millions of patients globally. Given that we're first-in-class, we've intentionally pooled or assembled a team of industry veterans with a track record in drug development, market making, and winning, who are playing with their hearts and minds to deliver on what is a meaningful mission for us. It's a purpose-driven company. Now, the journey began over 20 years ago with the scientific work of Annexon Co-Founder, the late Dr. Ben Barres, former chair of neurobiology at Stanford University. Ben Barres and his lab discovered the beneficial role of C1q in the classical pathway in early development, driving the removal of excess synapses to ensure appropriate neuronal circuitry and function so that we can all go forth and conquer the world. It was a groundbreaking discovery that our immune system played a key role in sculpting our brains and vision. Ben Barres and his lab went on to discover next that C1q accumulates on synapses as part of the aging process in all neurodegenerative diseases or in all of us, and is aberrantly triggered, which results in the removal of functioning synapses that are necessary for sculpting the brain and for sculpting vision. This was a very important discovery and really led to the formation of Annexon, where our goal was very clear to stop C1q right where it starts on diseased tissue to preserve function. Full stop. Annexon was later founded in December 2014 to develop this platform approach, and since has studied this mechanism of action in a host of diseases with diverse drug candidates. We've created more than 40 de novo assays studying C1q and the entire classical pathway in the specific diseases in which we are pursuing to really help understand the best way to target these really high unmet neurodegenerative diseases. That has led to a robust and highly consistent preclinical package, which is the underpinnings for all of the clinical programs in which we have pursued. We have not gone directly to the clinic. We have studied these diseases first in the preclinical setting to really inform what we did in the clinic, and we're happy to report that we've seen real significant consistency between what we've done preclinically and the ability to replicate that clinically in both acute and chronic diseases in a wide range of patient populations. With these learnings, we're more energized, and we're closer than ever to really demonstrating or delivering on our promise of ushering in a new class of immunotherapies to treat these neurodegenerative diseases across the globe. Today, our scientific foundation is translated into two late-stage registrational programs with blockbuster potential in large underserved markets. GBS is our most advanced program, having demonstrated the first placebo-controlled data set in this devastating acute neuromuscular disease in over 40 years. There, we're blocking C1q inflammation, both in the body and in the brain, to provide complete protection against this inflammatory cascade, and that's resulted in a landmark phase III pivotal win where approximately 90% of our patients improved by week one, which translated to a 2.5 times greater likelihood to returning to a full state of normal by month six. Really unprecedented findings in this disease. We've now gone on to file for regulatory approval in Europe, and we'll be filing thereafter in the U.S. GA of course, is next in line, where we're targeting C1q. This ties specifically in the retina to preserve synapses and neurons to protect against vision loss. We demonstrated this in our phase II study with Dr. Wykoff, who will review, and we're looking forward to our phase III data readout in Q4 of this year. There's more to come out of this platform. Behind our two lead programs, our programs are focused on small molecules targeting this inflammatory cascade in the body, and we're also targeting a host of neurodegenerative diseases in the brain like Huntington's disease, ALS, and TBI, where we have robust preclinical packages and, in some instances, early phase II clinical data as well. We're quite as serious about our mission of helping millions of patients suffering from this devastating disease. You'll hear more about the cascade later, but I just wanted to quickly punctuate that by targeting C1q in the classical pathway, it's a significant competitive advantage over downstream complement approaches that you are likely familiar with, like C3 and C5. That's because C1q is a recognizing molecule that localizes on diseased tissue. It anchors and activates this entire inflammatory cascade, which amplifies over time. In other words, it gets far more aggressive and deadly as it moves on. Only by stopping C1q, again, where it localizes on diseased tissue, can you stop all of the downstream inflammation associated with the classical complement pathway. As a result, this approach is the earliest and most complete protection one can provide against neuroinflammatory damage. Given the broad applicability of our platform, we've developed a diverse late-stage pipeline of neuroinflammatory diseases that we're pursuing with a diverse set of drug candidates. Each of these drug candidates, we've taken learnings from each of these drug candidates to inform the overall platform and to give ourselves a greater likelihood of success in each of the respective indications. We've seen that now by, again, targeting GBS and stopping this cascade right out the gate, as well as in Huntington's disease and other programs. We're really excited by that. Today, however, we're focused on vonoprument for the treatment of GA and for good reason. GA is a leading cause of blindness, as you well know, that unfortunately afflicts 8 million people globally, making it a major blockbuster market where scores of patients need an effective therapy to protect against vision loss. Vonoprument is designed to do just that and drive immense value for patients and shareholders by, again, protecting the structure that is associated with visual acuity in this disease, which translates to robust vision protection on a host of measures and patient populations. We also like its differentiated profile from a safety perspective, being a non-PEGylated fab fragment, with really nice penetration, and you'll hear more about that in time. We look forward to coming back to you later in the year to do a robust update on the market opportunity for geographic atrophy. It's immense. This is a population, patient population that's motivated for a treatment. Concerns around vision ranks high in this population, and we look forward to providing them a treatment. With that wind up, I'm gonna pass the baton over to Dr. Lloyd Clark, who'll give an overview of the GA clinical market. Lloyd. Oops. Sorry. Lloyd. It happens. Yeah. Thank you, Doug. Well, good afternoon. I'd like to thank you all for coming. I'm Lloyd Clark. I'm still a part-time practicing retina specialist, been involved in drug development for over 20 years. I've joined the Annexon team to work on ophthalmology strategy and innovation. Really excited about our program as we have the opportunity to bring a transformative therapy to the market. An important takeaway for today is to make sure you understand that geographic atrophy is a neurodegenerative disease with central vision loss, and we currently have no approved vision-preserving therapies. This really is foundational to our company and foundational to our program. These patients continue to lose vision in our practices, and this is the highest, the largest unmet need in retina today. These patients have significant symptomatic problems. They develop gradual loss of vision, and then later in the course of their disease, that vision loss can be quite dramatic. They have difficulty in low light settings, which is an important clinical finding, and these symptoms start out mild but progress to more severe symptoms later on in the disease state. Although these patients are somewhat older than our patients with exudative diseases, with the increased life expectancy, the number of these patients continues to increase in our clinical practices. This is a major issue for us as practicing retina specialists and a tremendous opportunity in drug development to provide meaningful therapies for these patients. Again, GA is a chronic progressive neurodegenerative disease. The figures on the right-hand side of your slide are two color fundus images or color retina images that look at the back of the eye. In the middle of the slide, you see an eye with a normal retina. That sort of regular orange-brown color is normal for the retina. On your far right, you see a patient with a large geographic atrophy lesion where you have almost total loss of the underlying retinal pigment epithelium. We know that GA is a neurodegenerative disease and that photoreceptors are lost first. That's what leads to vision loss. Later, these patients lose underlying retinal pigment epithelium, a lagging indicator of disease activity. We've asked patients about what's important to them as they think about geographic atrophy. When they're asked about the three activities that they're most worried about doing or struggle with, those include activities of daily living, recognizing faces, driving a car, watching TV or reading. These are real-life activities that these patients struggle with and ultimately affects their ability to live independently. What do they most worry about? Well, by far the leading answer is loss of independence for these older individuals. Again, the loss of the ability to perform their activities of daily living is key to these patients. This is an important problem for our patients that we see every day in clinical practice. As Doug outlined earlier, this is a large disease state, about 8 million patients worldwide, about 1.5 million patients just in the U.S. that are affected with geographic atrophy and would be immediately benefited from a vision-preserving treatment. Keep in mind that one in 100 patients over the age of 50 have advanced AMD. This is a significant problem, the largest unmet need in retina, one that needs effective therapies for our patients. A minute about endpoints. Clearly, visual acuity is the most important endpoint in retina clinical trials. In short, ophthalmologists, retina specialists, we're in the vision business. We're here to protect vision and improve vision. You see a number of transformative products here on this slide for different disease states that have been approved over the last two decades. All of these transformative therapies were approved based on 15-letter improvements or 15-letter protection of visual acuity. This is a clinically meaningful and relevant endpoint for patients, as well as clinically relevant for regulators when we talk about transformative therapies. We'll talk more about the endpoint a little bit later. This really is key to understanding our program as a transformational program. We have to use the gold standard endpoints to demonstrate clinical benefit for these patients. With that, we're gonna start our formal program. I'd like to introduce Dr. Eleonora Lad. She's Vice Chair of Clinical Research and a Professor of Ophthalmology at the Duke Eye Center and the Duke University Medical Center in Durham, North Carolina. She's a practicing retina specialist, full busy clinical practice. She also holds a PhD in neurosciences and really is a world expert in the science that she's gonna present to you today, the role of C1q and the mechanism of dry AMD with GA. Nora, thanks for joining us. Thank you, Lloyd, very much for the too generous introduction. It's really a pleasure to be with all of you today. I know it's a really cold day, so thank you for joining us. It is a treat to talk to you about dry AMD and geographic atrophy and dive a little deeply into mechanisms of disease and the important role of C1q. I have a personal story behind I hope you'll enjoy and some really cool images. We all know geographic atrophy is important. You've heard from Lloyd, it's the biggest clinical unmet need in retina right now, and the treatment landscape's rapidly evolving. We have the recently approved C3, C5 inhibitors that are designed to stop RPE atrophy and lesion growth. These studies are based on human genetics that show the complement inhibition is a viable therapeutic strategy for GA. The C3, C5 inhibitors were designed to target the alternative pathway to preserve RPE cells and reduce the lesion growth. A structural issue. The protection of RPE has not resulted in preservation of vision in a predefined manner in the clinical trials, and we all know those data. Now, fortunately, in retina, we have recent advances, and these are advances in technology with Annexon therapeutics and also imaging. Photoreceptor neurons now are increasingly understood to be as the locus of disease based on OCT imaging and what's called ellipsoid zone image segmentation. Ellipsoid zone is a layer of mitochondria, and Dr. Wykoff will go into that in detail. The recent data shows conclusively that GA is a neurodegenerative disease amongst the list of all the neurodegenerative diseases out there that are very important to patients. This results in photoreceptor and vision loss. Loss of photoreceptors through the classical pathway C1q importantly precedes RPE loss. It's an early phenomenon. C1q is very important. You've heard all of us have it in development. It's very important. We otherwise would have had all these aberrant synapses. Some of us might still have them, but the C1q is very important developmentally. The problem is it becomes recapitulated in disease, in neurodegenerative disease. Today's opportunity that you'll hear a lot about is this vision-preserving therapy that will meaningfully improve patient lives. I like the word meaningful because what our patients care the most is vision. You'll hear a bit about that. Because this is what the patients look like. The normal ones are on the left. This is what a picture looks like, hopefully to all of us, with normal vision. We have a normal retina with intact structure and function. The photoreceptors are the light-sensing cells in the back of the eye that convert electrical signal and transmit them to the brain, to the optic nerve. The RP are the supportive cells underneath the photoreceptors, but they're pretty sturdy, and they degenerate later. However, in a retina with GA, we have loss of signals because the photoreceptors are missing or dysfunctional. The RP over time also degenerates in this area of atrophy that looks like that cookie cutter area that you saw in the back of the eye that Lloyd showed you. What that translates visually for our patients over time is what you see here, a blind spot. That's a central blind spot. They cannot see the faces of the dear family members, you know, cannot drive, cannot read materials or look at their phone. Really impacts their daily life. Some of these patients are very healthy until their nineties, but they're really impacted by GA. We didn't talk about the burden of depression and anxiety related to this, but also hugely important because vision, again, is so important to our patients. Now this is where the fun begins. I hope you're ready for a couple colorful images here. To orient you on the anatomy of a healthy retina in histopathology, this is human, and you can see this uniform layer of photoreceptors and synapses. This is a functioning structural well-integrated unit. We have here the photoreceptor cell synapses, the outer plexiform layer. You can follow this across. It's nice and intact. The cell bodies of the photoreceptors are stained in blue. That's the outer nuclear layer. The retinal pigment epithelium are those sturdy supportive cells underneath. That's a normal retina. What happens in GA? This is complex, so we'll take this slowly from left to right. In an intact case, similar to the prior image, intact photoreceptors, intact synapses and cells, and you can see this nice layer of synapses and the cell bodies and RPE. This is an eye that has GA, which is way on the right. In between the normal area, and this is actually technically intermediate AMD stage in this eye, the zone of intermediate AMD, if you will. It's still functional, but over time, you see declining photoreceptors. They become thinned out, their synapses are missing increasingly, and their cell bodies become rarefied as well. The RPE also becomes more irregular, sometimes hypertrophy then becomes thinner at the edge. This is an area of geographic atrophy, complete loss of photoreceptor synapses and RPE. Synapses are gone, the cell bodies are less, and then the RPE is completely missing. The loss function corresponds with that blind spot that you saw in that image. Now, going back to the pathway, the therapeutic pathway that we're addressing here today. This is my personal story. I did residency at Stanford, and right after I moved to Duke to do fellowship and stay on as faculty there, I was reading the papers on the right because they started coming around right before Annexon was starting out as a company. I was really impressed with this MOA. My background was in neuroscience, so I read the papers with great interest because I thought this molecule was fascinating. It plays a key role in neurodegeneration broadly. Again, it's important in synapse elimination development for all of us, but later on it goes haywire. It's pathogenic in neurodegenerative disease with aging and the pathways get recapitulated abnormally. C1q inhibition protects against synapse loss and neurodegeneration, and that's the basis of the research presented to you today. This functions very well in a list of diseases. We're talking about dry AMD today and the photoreceptor damage in the patients, glaucoma, retinal ischemia, Huntington's disease. These are really terrible debilitating diseases that can be addressed with this MOA. ALS, Alzheimer's, and traumatic brain injury. You can see all the high impact publications on the right, and they speak for themselves. These are really good animal models of disease and really important data over the year. Dr. Ben Barres was the chair of neurobiology at Stanford, and also a member of the National Academy of Sciences. This is just really, really exciting MOA. You've seen this slide before. Now, C1q inhibition works at the top of this complement inhibition, the inflammatory cascade, because what it does, again, C1q attacks functional synapses. They're perfectly good otherwise for removal in disease, so it's aberrant. It activates the classical pathway. It attracts microglial cells, and I'll show you some examples of these beautiful cells, but they're not helpful in this disease state, driving neural death and resulting in loss of vision in patients. In contrast, and that's really important and exciting to understand, C3, C5 are downstream in the alternative complement cascades. They're removing dysfunctional cells at the edge of GA, driving cell clearance of RPE, the alternative pathway, and this happens after the photoreceptor damage and loss happens. These dysfunctional RPE cells, also important to understand, secrete VEGF, so you have an increased CNV risk with inhibition of C3, C5. Going back to some histopathology here, you can see on the left an image of a retina, where C1q is closely associated with synapses. C1q is in green, synapses are in red. That could be good color coding for the next image. Same thing happens in the brain, in CNS in Huntington's. You can see the exact confirmation of the synapse with C1q binding this closely. It apparently binds to synapses in neurodegenerative disease and triggers damage and elimination of these synapses where this should not happen. On the right, there's some really promising phase II clinical trial data in Huntington's disease, and you all know that's a debilitating neurodegenerative disease. The patients decompensate functionally and cognitively over time. However, C1q inhibition stabilize these patients over nine months in on and off period. From what I remember from neuroscience, that's a really difficult thing to do, and it hasn't been accomplished in this terrible disease. Again, the MOA works very well in HD and looking forward to seeing more promising data there soon. Back to retina. C1q again recognizes and eliminates good photoreceptor synapses. They would be really good otherwise. This is data from a light-induced murine model of photoreceptor degeneration. On the left, you can see a healthy retina with nice synapses and photoreceptors. Then in the light damage model here, the synapses are really thinned out. You can see there's less red here. A ton of C1q in green that binds the synapses, attracting all these microglia, these pink cells with processes, and they're causing damage functionally to the synapses, and that's why they're missing. Quantitatively on the right, you can see a decrease in synaptic density in this animal model of light damage. Does this happen in humans? Yes. Before we get there, so one more slide on how C1q inhibition helps. Vonaprument reduced inflammation and preserved photoreceptor synapses and cell bodies. You can see the control on the left with tons of inflammation from these pink microglial cells, a ton of C1q, synapses are really ragged, and C1q inhibition has a C1q abolishing effect here and much less inflammation. The quantification of the microglia shows they're reduced in numbers, the photoreceptor synapses are protected, and you have protection of the cell bodies as well. Functionally, not just structurally, you see protection of retinal function on electroretinograms in these animals. Does this happen in human? Yes. This is an image from a GA patient, again, back to histopathology, and you have here the C1q deposition on the synapses. The green with red gives you colocalization in yellow. You can see what happens. This is a microglial cell body. It sends its processes actively in this area of synapses, and right there they're missing because they are being chewed up by microglia. Similarly, this area, you can see the topographic localized loss related to a neuroinflammation. Going back to progression of disease, I showed you the complicated histopathology slide. This is a nice diagram. We'll take it easy from left to right because I think that it makes a lot of sense. Think of this as happening in the same eye that illustrates zones of disease from intermediate, namely normal to intermediate to GA, and also shows disease progression in the same eye. Again, from left to right, we have an area of functional photoreceptors with intact synapses, intact RPE. The next stage, as you move towards GA, you have the RPE is intact because, again, this cell is quite sturdy and degenerates late. But the ellipsoid zone, it starts to be coated with C1q and the photoreceptors as well. Over time, C1q binds the photoreceptor synapses leading to vision loss. This is why the patients are starting having all the symptoms Lloyd talked to you about over a period of time. Later in this, in the disease process, you can see the photoreceptors become highly dysfunctional structurally as well, and then C3 and C5 come in because they start to clear these dysfunctional photoreceptors and also the RPE cells that now become affected at the lesion edge. Right at the edge of GA, you have a lot of C3 and C5 deposition. Again, remember, C3, C5 targets dysfunctional cells, so the inhibition addresses that at the lesion edge after the photoreceptor damage already occurred. Then in the GA, you can see this is bare bones. Basically, you only have Bruch's membrane, RPE, photoreceptors are completely gone. This is irreversible. This is why GA is a neurodegenerative disease. You do not get restoration of photoreceptors. They're terminally differentiated neurons like in the brain. You cannot restore function. That's why I think the impetus is addressing the disease early in the zones before four. By four, it's too late. In summary, GA and vonaprument's role in protecting vision loss in GA patients. Blockage of C1q is meant to stop photoreceptor damage at the genesis before the disease is irreversible and late. Vision loss in GA is driven by photoreceptor synaptic and cellular loss. This is neurodegeneration. You have photoreceptor damage and vision loss. Again, this is before RPE atrophy. It precedes RPE atrophy targeted by the recent complement inhibitors FDA-approved currently. C1q is an aberrant upstream trigger. It's quite different from this neurodegenerative process in GA, so it's a differentiated MOA from the current approved drugs. It tags this functional, perfectly good photoreceptor synapses and cells and dooms them for removal. You have the whole activation of the cascade. You have a cellular microglial recruitment and neuroinflammation galore with synaptic loss and irreversible vision loss. We want to be ahead of it by inhibiting it. Again, this is, there's a clear mechanistic differentiation between C1q inhibition and the inhibition of the downstream complement inhibitors. Upstream, we have protection of photoreceptors necessary for visual acuity, so very, very different mechanism. This allows for normal clearance functions of the alternative pathway, so it keeps those intact downstream or more intact downstream, and they're helpful. A downstream C3, C5 slow RPE lesion growth but do not slow vision loss pre-specified in the phase III clinical trials as you've seen. With that, we will talk about the clinical data. It is my true pleasure to introduce Dr. Charles Wykoff, busy retina clinician and Chair of Clinical Trials for Retina Consultants of America, the biggest retinal practice in the United States. Charlie. Thanks, Nora. All right. Hello, everybody. Good afternoon. Great to be here with the whole team. Nora, that was an amazing overview of the science, and I think it fits really nicely with the clinical data that we'll see. You know, before I dive into what I have to share, I'll just give you my perspectives on the field. You know, it's a fascinating and a really important pivotal time in retina, specifically for GA. I mean, if you look at the pipeline of drugs across retina, there's more in retina than ever before. But by far, from what I can see, the majority of that is in GA. There are good reasons behind that, and Lloyd and Nora just beautifully laid out what those are. Patients wanna maintain more vision tomorrow and the day after that. They really want vision, and we have a huge unmet need to give them that opportunity. When you look across the trials, this one holds a key position because it is the next most important one to come out. There's actually a lot of datasets, probably 12 really important datasets across retina over the next year to 18 months. It's a fascinating next year. This is the most important one from a GA perspective because it is truly a differentiated MOA, has the opportunity to provide visual benefit to patients, and it's the one that people are thinking about because it's the next phase III trial that's gonna really inform what could be for patients. Okay. Let's take a deep dive into what the drug is, then we'll talk about the phase II clinical trial, both the anatomic and the functional outcomes. Vonaprument is ANX007 as I would rather call it because I can't quite pronounce that yet, so forgive me. This is a small biologic. I can tell you from a physician perspective, we like biologics. We've been using biologics in this space for 20 years. They have an incredible safety profile in our hands, and that is attractive to me. 50 kilodaltons. Importantly also, it's non-PEGylated, low viscosity, and it's a small volume. In the phase III clinical trial, all patients are receiving 25 microliters per dose. That's a very reasonable volume, lower actually than any of the anti-VEGFs, which is great because the lower the volume, the less fluctuation in IOP for patients, which can be an issue. As we'll show in the phase I data in a second, most importantly, we're seeing good pharmacokinetic and pharmacodynamic signaling here. It's fascinating and the complement cascade is complicated, and Nora describes it in a beautiful way. It's fascinating because in some discussions you think about, well, let's target the alternative cascade, and that's the whole goal. The whole goal here is actually the opposite. It's to preserve the alternative cascade. I think we as a field are still trying to figure out where do all these things play. I think the mechanism that we're talking about today, importantly if you understand, is actually preserving some of the important physiologic roles of the complement cascade in the back of the eye, which may very well be important for long-term health and optimal functioning of the retina, even in the context of GA. This is the early human clinical trial data that gives us an indication of pharmacokinetics mostly. The blue bars here are the sham-treated patients. These were actually glaucoma patients that got a single injection in red. The red arm was 2.5 milligrams and 5 milligrams given once at day one. You can see complete target engagement there with this small format biologic after 29 days. A month after an injection, you're still getting full target engagement. That's impressive. You're not bouncing back, suggesting you could at least do monthly dosing, and commercially, maybe there's an opportunity for significantly less. Let's dive into the phase II clinical trial data, ARCHER. Here's the design. You've been seeing this for years. Gold standard clinical trial design. 270 patients, so a large trial. Sham-controlled patients are in gray through all of these graphs that I'll show you, and then the two active arms in red and blue. The red is every month dosing with 5 milligrams, and the blue arm is every other month dosing. Importantly, really important in geographic atrophy trials to understand who is the patient population that's been enrolled. In this patient population include patients with both foveal involved GA lesions and non-subfoveal lesions, and we'll talk about why that's important. Randomized, double mask, and gold standard design. Primary endpoint was looking at GA growth based on fundus autofluorescence. We'll talk about that, and then a lot of pre-specified endpoints related to function. Really nice trial design also because there's this six-month kicker at the end. You get 12 months of active treatment, but then a really nice scientific design there at the end where you have six months off treatment that really gives us an indication of the disease-modifying potential of this drug, and we'll come back to that as the last slide of this dataset. Okay, so here's the baseline characteristics overall. Well-balanced between the arms. No outliers here. Average vision was about 20/70 in each arm. Visual acuity was, or foveal involvement was at about 50% of patients. So half of the patients had GA lesions that involved the center point of their vision. Average size was 7.3 mm², and the majority of these lesions were multifocal, and about a quarter of them had wet AMD in their fellow eye. Another important thing to notice, because some trials exclude those patients with wet AMD in the fellow eye, especially programs that are worried that their drug may cause wet AMD conversion. This one did not exclude that in the fellow eye. Okay, let's go through the anatomic outcome squarely, and then we'll dive into the functional outcomes. This is the primary outcome data here. As you know, this primary endpoint was not met. This was the rate of change of GA lesion growth as measured by fundus autofluorescence, right? We'll talk about two major imaging modalities. FAF, or fundus autofluorescence, is what was used to gain FDA approval of the two commercially available drugs for GA currently. Essentially it's measuring RPE cells. It's measuring the lipofuscin collected in RPE cells over time. If you look on the graph and you double-click on it and you look closely, you see, well, is there a separation there, right? Is that red line separating a little bit? The answer is maybe. You know, numerically, it's 6% slower growth than the control arm with monthly dosing. Then if you look at the right graph, this is where this may be reflection of the pathophysiology that Nora beautifully described. That is, there appears to be no benefit on slowing GA lesion growth from an RPE perspective in the first six months. If you look at the second six months, there is a signal there. What that might be suggesting is that if you preserve photoreceptors, right, by inhibiting C1q, and you stabilize that visual transduction signal through photoreceptor protection, maybe then you get secondary protection of the RPE cells, right? They're in complex. These photoreceptors and RPE cells have a very close relationship. If you stabilize one, the photoreceptors, which we know are dying before the RPE cells in this disease process, you very well may subsequently protect the RPE cells. I like that signal here, and it tells me if I did a longer trial, 18, 24 months, that's where I would expect to see further separation of this curve focusing on RPE cells. Really important subpopulation of patients for a lot of reasons. This is looking at patients with subfoveal lesions, right? These are patients where the GA has actually affected their central vision, right? When you look at me and you look at these slides, you look at your computer, right, you're using, yeah, your fovea, but you're using your center point of your fovea because the fovea is actually still an area, but center point is just a single dot in the back of the eye where you actually are reading from. All the patients included on this graph have involvement of that center point. It's particularly important because these patients are probably much more likely to experience a 15-letter loss or a 10-letter loss or a 20-letter loss because their fixation point where they're seeing from their high acuity area is actually much less stable. In this patient population, you're actually seeing a potentially larger signal of efficacy here of slowing GA lesion growth with fundus autofluorescence here. Again, you see that same greater benefit in the second six months than the first six months, up to 14%-16% growth reduction in that second six months among this subfoveal patient population. That's all fundus autofluorescence-based imaging outcomes. Really important to look at that largely, I think, from a historical perspective because that's where the field was headed for 20 years. I think we've become much more sophisticated as a field in thinking about geographic atrophy and intermediate dry AMD that a lot more information can be gleaned from the OCT. That's what I'm going to unpack here. Nora showed some beautiful images here. This is the OCT correlate of what Nora was showing, right? This is a cross-section through hopefully your and my fovea. This is a normal cross-section. This is about as thick as a human hair. If you pull a hair off your head and you hold it sideways, that's about how thick the human retina is. The photoreceptors make up about half of that thickness, right? The dark band there are the photoreceptors, and then there's multiple different layers of the photoreceptors, but the one that we're focusing on is the ellipsoid zone. That one is important because it houses all of the mitochondria, right? Photoreceptors are powerhouses. They are incredibly active at generating ATP. Vision takes a lot of energy, and those photoreceptors are packed into that small zone called the ellipsoid zone. Loss of that ellipsoid zone is a critical biomarker strongly associated with visual function in GA, in AMD, but other diseases also. MacTel type 2, for example. That's how revakinagene taroretcel-lwey, the Neurotech ENCELTO implant got FDA approved based on this biomarker analysis. Within the ARCHER phase II clinical trial, we took all patients that had Heidelberg imaging. It was 192 out of 270, and specifically quantified this photoreceptor health over time by looking at this ellipsoid zone. Here's what that data shows. This was across the entire volume scan. As we talk about these two imaging modalities, important also to think about the field of view. With OCT, we're taking a 6x 6 area. It's 6 mm on each side. It's a cube, essentially. Across that zone, you can see that with active treatment here, you've reduced lesion growth, GA lesion growth as focused on ellipsoid zone by 27%. Really interestingly, and something that took me a while to process when I first saw this data, is that this appears to change. The potential benefit of the drug seems to change depending on where you're looking geographically in the back of the eye, right? The whole volume scan is 6x 6 mm. If you tighten that in the middle and you come into a 2-mm diameter, and you tighten it more on the right and you come close to the central subfield here, slightly larger, 1.5 mm, you can see that those percentages of slowing GA lesion growth by focusing on photoreceptor EZ zone actually increases from 27% to 48% to 59% slowing of progression of the disease. Why is that? Well, I don't think you would see this with other drugs. I think you're seeing that specifically with this drug because the photoreceptors have a particular proclivity there in the center of the macula where this drug can be most beneficial. Let's show this on a specific patient example to kind of put this into perspective. This is a single patient in the sham population. Many patients would fit this, but this is just one for illustration. On the top left here is OCT cross-sectional imaging, and below that is the corresponding fundus autofluorescence, right? Top left, we're looking at photoreceptors, in particular the ellipsoid zone. Green is good here, right? The green is intact photoreceptors on Nora Lad's imaging, the sort of zone one and two, essentially, photoreceptors that are still working. Then in the black, you have total loss of the photoreceptors. You want more green. If you look in that central red circle, that's where patients' high visual acuity comes from. When they're checking their vision, that's what they're seeing with. When you look at that, you think, "Okay, there's about 50% of that red circle is green." Then if you go forward to 12 months in this sham-treated patient, you can see you've lost most of that green in that central red circle. You can see now a much larger area of black in that zone indicating photoreceptor loss. That corresponds nicely in this patient with a loss of vision from 66 letters down to 51 letters. This is an irreversible progressive decline. A 15-letter loss is a very meaningful loss for patients. This is a life-changing event where they've lost half of their visual function. In parallel there at the bottom on the fundus autofluorescence, that change in that central circle much less evident to the naked eye, right? What we're doing with OCT is we're able to see at a granular level what we think is actually happening from a visual function perspective. It's a nice link between the anatomy and visual function that I think is much more difficult to glean from fundus autofluorescence. In summary, from an anatomic perspective, and then we'll dive into function, OCT-based ellipsoid zone measurements have quickly become a key component of any AMD trial, and I think over time are going to really replace what we think of with fundus autofluorescence. They're probably the best way to link structure with function in AMD and many other neurodegenerative diseases, including MacTel and inherited retinal diseases. Okay, let's look at function. That's what patients really care about. We can show patients their imaging, but what they really will care about is what can I see today and tomorrow. This is the key endpoint that you've heard about before and is the primary endpoint there in the phase III ongoing clinical trial that we'll talk more about in a second. This is showing dose-dependent protection with active treatment at preventing visual acuity loss. That visual acuity loss here is defined as 15 letters lost. Left side and right side of this graph are showing the same thing, but measuring it in a slightly different way. Both of these are confirmed visual acuity loss, so patients have to have experienced that either twice on the left or at the last visit at 12 months. Then on the right, same thing. You have to confirm the visual acuity loss with two visits at any time point, including at month 12, when it would have to be repeated at month 15. The point is that you're seeing the same outcome regardless of how you assess this. When you look at confirmed 15-letter loss, you see a dose-dependent protection with active treatment. If we look at this on a Kaplan-Meier curve over time, you can see a 73% reduction in the risk of 15-letter loss, with every month dosing there in red, and importantly, you see an increasing impact over time. This is now a sensitivity analysis where you broaden the view. Before we were looking just at that 15-letter loss in the middle graph here, now we're adding on the 10-letter loss on the left and 20-letter loss on the right. Each of these has their own sort of important clinical and potentially regulatory discussion, which I'm happy to get into more later, but all of these I think are quite relevant. Then if you look at average visual acuity, right? Average vision on clinical trials, especially in geographic atrophy, I think can be challenging. But on average, you would expect in an untreated patient population, four to five letters of loss. We've seen that repeatedly in all the control arms, from all the GA trials over the last few years. Here you're seeing again, a consistent signal of dose-dependent protection and visual function, mean visual acuity there on the left, which is high contrast, meaning the lights are on for patients. Then on the right is the same protective benefit with treatment there in a dose-dependent fashion under a low luminance visual acuity setting. Worth talking about what we mean by low luminance. It simply means that you've turned the lights down. You put a filter over their glasses that they're using to check vision that prevents a certain percentage of light from going in, so it's a darker setting. You think, "Well, why is that? Why are we turning down the lights to measure these patients?" You're doing it to stress the visual system. As Nora Lad pointed out, in that zone two, zone three, there are still some functioning photoreceptors, but they're on edge. They're not doing as well as they would in zone one. If you stress them, if you give them less light, you actually can see a greater deficit in these patients over time. Diving into that low luminance setting on this slide, on the left, you're seeing the same dose-dependent protection here, with active treatment every other month and then every month in blue and red, decreasing the portion of patients that are losing 15 letters of low luminance. On the right, low luminance deficit, again, showing the same dose-dependent protection. What is low luminance deficit? This is important because the next slide will bring this out a little bit further. It's the concept of, well, what's your visual acuity, and then what's your visual acuity under the high luminance normal light setting versus low luminance, a darker setting. A greater difference there suggests more advanced disease. I'll go to that first. If you look at low luminance deficit now in a specific threshold, these are patients that have theoretically less advanced disease. In other words, their low luminance deficit is smaller. This has been defined in other trial programs before, probably first in the lampalizumab program. You can see that in this population of patients, which maybe we could call earlier in the disease process, even though they all have GA, these are slightly less advanced GA patients. We see really a potentially profound effect of drug treatment here with none of the patients in the every month arm experiencing a 15-letter loss. If we then look at hazard ratios for all the baseline characteristics, you can see consistent potential evidence there of drug benefit with monthly dosing there in red and every other month dosing on right. Again, these are all the baseline characteristics related to function and phenotype, for example, specific phenotypes that may bring out more aggressive disease, such as diffuse-trickling and the presence of pseudodrusen. Okay, now some subgroup populations here of particular interest. The foveal and non-subfoveal patients, worth going into this a little bit of detail. Why is this relevant? Well, first, it's relevant because a lot of trials have excluded the patients on the left. They've completely excluded them. They did that in the field for an interesting reason. They did that largely because they were trying to show a functional benefit with their drug, and that has not been shown by any other drug yet in a pivotal trial. That logic may have been flawed, because in this case, where we think we're actually preserving visual function, we actually see more events in those patients. In other words, if your fovea is involved and you already have an involvement with the disease, where you are seeing detail with, those eyes become much less stable from a visual function perspective. Where they're seeing from is much less stable. It migrates around within the fovea and the perifoveal area. You see that on the left. The gray bar, for example, many more events of 15-letter loss. Really important enrichment strategy for a phase III clinical trial where you wanna have more of these events rather than less to be able to show a benefit with your drug. Importantly, you're seeing the drug benefit in both populations, foveal and non-subfoveal patients, but you're getting more of these events with foveal involvement. This is the last graph related to efficacy before we get into safety. This is often a favorite. I think there's a couple interesting points here. The most important is the scientific rigor of this to me. It's one thing to develop a head-to-head trial with sham where you have an active treatment arm, but it's unusual in retina to actually have an off treatment arm. We've seen this before in retina in a few select cases where it's been really useful, and here I think it's similarly useful. Why is that? Well, if you look in the active treatment in the first 12 months, you can see in the first six months there's not much separation of the curves, but then by the end of 12 months, you're seeing that separation that we've already talked about where the proportion of patients that have lost 15 letters is meaningfully lower in the blue and the red trajectories there at the bottom of the graph compared to the sham patients in gray at the top. What do you notice as you transition into the gray shaded area of the graph? You see now all of these slopes appear the same. In other words, events are happening now equally in all of the arms when you're off treatment, which is supporting this concept of drug efficacy. It's supporting the concept of a disease-modifying effect on treatment that goes away when you stop the therapy in the last six months. I think it's a really elegant component of this trial design. Really important to take a close look at safety across any retina program. We've seen a lot of safety challenges in many different areas of drug development in retina over the last five years. Importantly here, we're not seeing an increase in choroidal neovascularization. Remember that patients with wet AMD in their fellow eye were absolutely enrolled in this trial, and that is an increased risk factor to begin with, and you're seeing what you'd expect with natural history, probably a 3%-5% rate of wet AMD development over the course of a year in all of these arms. From a retinal vascular occlusion perspective, we had one patient on the every other month dosing arm that was not associated with any vasculitis. It was a central retinal artery occlusion believed to be related to other comorbid diseases with the patient. There were no cases of vasculitis, three cases of intraocular inflammation, all mild or moderate and resolved with a short course of topical steroids, and no cases of ischemic optic neuropathy. In summary, I think the way I would put this is that patients care about their vision. Of course, they care about their anatomy, but they really only care about their anatomy if it translates to visual benefit to them over time in this disease process. We've learned a lot about how to measure anatomy, about how to measure function over time. I think what you're seeing here is a correlation between anatomic preservation with an EZ-targeted approach here, and then multiple lines of evidence suggesting a potential disease-modifying benefit of preserving visual function, both high contrast and low luminance across patients in a on-treatment/off-treatment trial. With that, I will turn this over to Jamie and look forward to discussion. Thanks, Charlie. I'm gonna take a few minutes and talk about the phase III program with you. We can go to the next slide. The phase III study was directly based on the phase II program, the ARCHER study, which Charlie just shared the data with. We did this in order to ensure consistency across the entire program throughout time. The pivotal program is based on the global ARCHER II protocol, which is a schematic of which is depicted here. It is a double-masked, sham-controlled, randomized two to one active-to-control study. 659 patients have been randomized to this study around the world, including the U.S. and Canada, Europe and the U.K., as well as Australia and New Zealand. The primary time point of this study is reached when we have efficacy data available from all patients through 15 months. We completed enrollment last summer, which brings us to top-line pivotal results expected at the end of this year in Q4. The study will continue through 24 months in a masked fashion at the patient level, and those data will be subsequently available. The single protocol importantly serves as a registration package globally. In Europe, the EMA supports the use of a single analysis from this study, and the single study for registration. We have been granted PRIME designation, which stands for priority medicine, from EMA, which actually underscores both the unmet medical need as well as the potential opportunity that a product like vonoprument represents to them, which is well-recognized in the U.S. In the U.S. perspective, we have been. The FDA has also agreed that we can conduct this study under the single protocol. One study under a single protocol, but they've also recommended that we divide this study, that we assign sites to two independent studies, once the study is completed, and that allows us to run two analyses on sub-studies to meet their historical precedent for requiring two studies for registration packages. That allows this one program to be able to serve both the European and U.S. registration. As I said, we conducted this study, highly parallel to what we did with ARCHER, but we did take the learning from the data that Charles just shared, and three things stood out in particular when we designed the phase III program in this. The first is that patients who had low baseline vision were far less likely to lose 15 letters. In other words, they'd already lost a substantial amount of vision, and they were just unlikely to lose additional visual acuity over the course of the study. Given that, we've excluded patients who have BCVA of 45 letters or less at baseline, and that corresponds to about 20/20 vision. Additionally, we noticed that patients with foveal lesions were much more likely to have 15-letter loss events, and Charles Wykoff showed those data. We have enriched the data set in the current ARCHER II program to include a higher proportion of patients with subfoveal lesions, which allows us to have a higher rate of events in this study and better likely to show a treatment effect. Finally, also in the last graph that Charles Wykoff showed you, patients continued to lose vision beyond 12 months, especially in that sham group. By extending the primary time point to the 15-month time point, we ensure a steady stream of patients will continue to lose vision over the course of this study to be able to better demonstrate a treatment effect from vonoprument. Now, this means, taking all these things together, what it means is that the phase III is a highly powered study. The single study is highly powered, as well as the two sub-analyses that I shared with you are both highly powered in terms of phase III standards. Finally, I also wanted to highlight some ongoing work that's with this program that's being done in a masked way. First, we're tracking the number of events that are occurring within this study, and those events are accumulating right on track to what we both expected from ARCHER, from the phase II study, but also what we predicted for the ARCHER II study, for the phase III program. We're right on track with events, which is a very good sign. In addition, we've also noticed that we're retaining patients very well. This study is keeping patients in the study better than other studies in the field, and that just speaks to the quality of the ongoing execution of the program. Then finally, we have ongoing safety surveillance also in a masked way, but we have had a data safety monitoring committee watching this study in an unmasked way, and they've given us, and they have met recently and basically have said there's no signals for which we require any changes to the protocol, and we just continue as is. We're on track to deliver the results as I've shared. With that, I will turn this back over to Doug. Nice job with that. Well, I wanna thank the speakers for the prepared remarks. We're gonna now move into a roundtable discussion with our experts. They'll tee up a couple of topics to talk about, and then we'll open it up to the audience for any questions that you may have. Doug, thank you. Thank you very much. Okay. Dr. Lad, Dr. Wykoff, Dr. Danenberg, and then I'd like to introduce Ted Yednock on the end. He is Executive Vice President and Chief Innovation Officer of Annexon, has done incredible work on a lot of the basic science that you've seen in his team. He's got a very talented team, and they've done some outstanding work in terms of understanding the disease state, understanding and really establishing this as a neurodegenerative disease. Great work. We'll hear from our panel on a few questions that we've prepared, and then we'll give you guys an opportunity to ask some questions as well. I'm gonna start with the endpoint. You know, our endpoint is confirmed 15-letter loss of visual acuity. You know, Nora, what does it mean to a patient when they lose 15 letters of vision? I mean, what do you see in the clinic? What do they experience? 15-letters of vision loss is really debilitating. When they come in, they're very distressed. Charles Wykoff and I had this conversation. They're really anxious. They don't know what's happening. As retina specialists, we do a full workup. I mean, we do fluorescein angiogram, ICG. We wanna make sure there are no other causes. But if it's GA progression, which is likely this is, involving the fovea, and that's the worst case scenario, their central fixation's gone. Suddenly they cannot see faces. They cannot read. They cannot drive. It's a huge loss to them. I mean, it is highly reproducible also in our clinic measurements, and it's meaningful. I mean, it takes a great toll in their life. Yeah. One of the observations that I've had as well is that, you know, these folks, once they lose a certain amount of function, they're not independent anymore. When they come to see Nora in the clinic, they've got a family member, or they've had to hire a driver. These are serious impacts on their quality of life. Can you speak to other, you know, sort of direct quality of life issues you hear from folks? Well, they're just afraid. They don't know if their life will suddenly change, if they can continue to be independent. They do come with a family member, and they're very distressed. I think it has a broad impact on their life. Oftentimes, at least in North Carolina, people live a long time now, and they're quite healthy. GA is so debilitating to them. I mean, it's one of the greatest fears, I'd say. Vision loss is one of the patient's greatest fears in life. Yeah. I think we've clearly established that geographic atrophy is a major problem, biggest unmet need in retina. We also understand that the loss of 15 letters of vision is, has a profound clinically relevant impact to patients. We know that from dry AMD, but we've known this over the last 20 years as we've been involved in drug development for the more commonly treated diseases, such as age-related mac, wet AMD and DME. It's very clear that this endpoint is highly clinically relevant to patients. What about regulators, Charlie? What does this 15 letter loss mean in terms of designing? You know, you've designed dozens and dozens of clinical trials. You've run over 300 as a principal investigator. What does this endpoint mean in terms of designing clinical trials, and what does it mean to regulators? Yeah, I think two things. One is it's highly reproducible, as Nora pointed out, and the FDA has stood behind 15 letters as a clinically relevant threshold for a long time, and they have not budged. I mean, we've all three of us have been in rooms directly with regulators trying to actually convince them, "Look, we can go to 10 letters. 10 letters is also quite meaningful," 'cause it is clinically. But they have always stood fast on the, "Nope, we want 15 letters." There's rationale there, right? What that means is that it's a doubling of the visual angle. So what does that mean for you guys? Well, if you're sitting 100 ft away from us and you're looking at us, what does that mean if you lose 15 letters to you? It basically means you have to walk half the distance towards us to see the same thing, means you're losing half of your vision, and they like that quantification. They like that doubling of the visual angle because you've lost half of your visual function, and they like that absolute threshold of like this is definitely a meaningful quantitative measure. Yeah, one of the wrinkles. There's a lot of different ways to look at visual acuity. There's several different ways to look at 15-letter change, in this case, a 15-letter loss. One of the key observations that we had in the phase II study was that when patients have 15 letters of loss in this disease state at two consecutive visits, they don't typically come back. This really eliminates the noise. Is it important, you know, when we talk about, again, designing clinical trials, when we talk about talking to regulatory bodies, is it important to have a reliable endpoint? You know, there is quite a bit of variability in these patients, but the goal here, can you comment on the goal of eliminating noise in an endpoint like this? If you're a regulator, you wanna make sure that what you're approving truly has the benefit that it's purporting, and so you wanna pick a threshold that's going to be consistent. To make it reproducible, say you don't have to lose 15 once, but you actually have to lose it twice, is quite a meaningful threshold. There's a reason why we don't talk much about five letters lost or gained, 'cause that can be all within noise. Once you're sort of in that 15 and above range, it's pretty reproducible, and that's why regulators like to use it, 'cause you do minimize that risk of noise. Yeah. Nora, let's presume we have a, you know, we'll run the clock forward into the year and we have a drug that protects 15-letter loss in a statistically significant manner. What does that? How do you apply that in clinical practice? You have a busy practice, see lots of patients with dry AMD. How would this impact your decision-making when you see these folks? I think it'd be game changing, to be very honest. That's what the patients are asking for now. What can we do to slow down my loss? How can we prevent me from losing vision? I want to stay independent. I want to be able to do things I enjoy. I think it'll be game changing. I think, their risk-benefit profile is critical, so if we can prevent vision loss reproducibly earlier in the disease process would be key, and then having less, risk of complications like choroidal neovascularization, you know, wet AMD formation with lots of injections because that also takes a toll on their life. Mm-hmm In terms of coming in frequently for appointments related to injections and the rest because the clinics are busy, but so are patients. They're active in their communities, and their family members who bring them are also busy. I think it'll be they can maintain their lifestyle and ability to do things they enjoy and not have to come see us as much as we enjoy it. We practiced in an era where we had replacement drugs, for lack of a better term. You know, we had, you know, Macugen, for example. You know, it was approved by the FDA for AMD, and then once we had more effective anti-VEGF agents, those drugs really became standard of care. Is this an addition to the armamentarium that you see today? Is this a replacement drug? What do you do with patients that are, you know, are treated currently with downstream complement inhibitors? How would you integrate this? Right. It's a great question. That's gonna get more complicated over time, hopefully if more options become available. The way I would answer that is I am a big believer that the current medicines that are FDA approved and commercially available are useful. I think it's important to slow this disease process, and so I offer them, I talk with my patients about them, and I use them clinically. That said, every patient with GA, if you talk to them and you listen to them, and those in the audience that haven't, I encourage you to, they are very eloquent in describing what we're talking about, much more so than we are. They describe vision loss on a daily basis, not like a once every few months when you lose 15 letters. They notice it every day that their vision is slowly creeping away. Even though I'm treating them with the current FDA-approved therapeutics, they still bring up, "I'm losing vision." I kind of say, "Look, I think, you know, we're doing the best we can. You're getting the best drugs available." If there was a drug that had on-label vision protection, it's a very different discussion with patients than a circumstantial, "Well, we're slowing the progression of the anatomy so that we can hopefully preserve your vision." To be able to talk directly and bluntly about on-label vision protection would be a very different scenario. Do you think it would impact the number of patients that you actually treat? I think it would broadly change how physicians think about treating GA. I think a lot of physicians are unfortunately currently turned off with the current options because of the risk-benefit ratio in some cases and because of the lack of prospective visual benefit in the core phase III clinical trials. If you change both of those factors meaningfully, yeah, you're gonna change the market opportunity, which is good for patients. Well, when Charles talks about the benefit-risk profile, Nora, I think we understand the benefit component to that in terms of really a different type of benefit in terms of functional benefit, let's talk about the risk side. I think one issue that's important here is the rate of choroidal neovascularization, right? I mean, in the phase II studies, there was no increased CNV risk in these patients. Give us a sense of what that would mean to you as you make treatment decisions. I think that'll be very important to patients. They like to be safe, so I have a thorough discussion about risk, benefits, and alternatives every treatment that I do. I go over the clinical trial data in as much details I can within the allotted chair time, which is limited these days in the retinal practices. I think it'll be so reassuring to have this great risk profile and side effect profile so you don't have an increased risk of CNV in these patients. Then they know they're not gonna have to come in as much and get additional injections on top of the ones that have a protective effect to the retina to maintain their good vision. Everything Charlie said resonated with me because I actually hear my patients saying pretty much the exact same things. Yeah. A real opportunity for improvement. Charlie, you gave a great sort of perspective on where we are today. Any other final comments about sort of the current landscape? Not just clinically, but also in terms of, you know, the importance of sort of moving the- Yeah Moving the field forward to try to find better functional outcomes for these folks. Man, I would tell you it takes a team, and those of you sit in the audience are a key part of the team. I mean, someone's gotta fund these projects, and I think that, you know, to be able to benefit patients, there's a lot of shots on goal out there right now, and hopefully more than one will work. I really hope as you guys do your diligence out there, you look for programs that are gonna improve visual function for patients 'cause that's truly what they care about. I'm a big believer in using ellipsoid zone. There's actually an approvable endpoint. That's not what this project's doing. That it's an important sort of part of the package here. They're focusing on vision, which is even more important. Very interested in sort of understanding ellipsoid zone better over time. Really, when you look at programs, ask, "Okay, functionally, what are we gonna demonstrate here?" 'Cause that's what patients really care about. Great. Let's talk about the product. Let's actually talk about the product formulation just a little bit. You know, Charles Wykoff went over some key differentiators in terms of vonaprument improvement relative to current therapies, right? There are some obviously factors that are important from a biologic perspective, and those are certainly important, and we've talked a lot about the complement cascade and how this drug works upstream in terms of protecting photoreceptors first. Let's talk about some of the practical issues 'cause some of these are important to us as clinicians as well as to patients, and they may not be readily understandable. What's the value here of small volume, right? You know, we've got drugs that are available anywhere from 0.5 cc's all the way up to 100 microliters. Mm-hmm. This drug is delivered in a small volume. What does that do for you in clinic? Does that give you flexibility? Does that help you in certain clinical circumstances? I think as Nora Lad pointed out, most retina specialists are busy. There's a lot of patients with a lot of injections being done, and so anything to minimize risk and improve that efficiency is good for patients. With drugs that are over 50 microliters, there is a change in that risk profile. We've seen that with 70 microliters with recent anti-VEGF. We've seen that with 100 microliters with some of the GA drugs, both the GA drugs. What that does is it just adds another level of complexity. You can certainly deliver all those drugs safely, but you just have to think about things a little bit differently. 'Cause every patient's different. Some have high risk glaucoma. Some go dark with the injection. You've gotta think about the physiology of the eye, and when the pressure goes up with the volume, you put any volume into the eye, the pressure is going to go up by definition, simple laws of physics, and the more volume that you put in, the more we worry about that pressure fluctuation. It just adds another level of complexity. Doesn't mean you can't do it safely, but to have lower volumes overall is going to be preferred by physicians. One clinical scenario that is certainly identified by us as retina specialists and fairly common are patients that have GA as well as exudative disease. Mm-hmm. There are opportunities where you can actually treat both conditions concurrently. Eleonora Lad, do you have patients like that? Yes, I do. The 25 microliters would be so easy. Otherwise you have to wait. Just give you the practical view here. It just takes a while for the IOP to come down with a high volume injection, 100 microliters. There's patient issues, so they don't like, you know, the vision dimming, and then it's uncomfortable when the IOP rises in the eye because the pressure sensation, they might need Tylenol or, you know, IOP lowering drops in clinic, but it also takes time. This is, you know, it takes up an injection room and technician time, so the whole staff is involved too, and it really slows down the clinic processes. Yeah The volume's gone up. I think it'd be hugely important to have the small volume. The IOP would barely go up, and then you can also treat with an additional anti-VEGF. Right If you have to. Yeah, the other issue is oftentimes we bring these patients back for multiple visits, so they get- That's right. ... a dry AMD injection on one day, a wet AMD injection on the other. Small volume GA therapy would likely eliminate a lot of these complexities. Any other comments sort of about the other thoughts about the drug product itself? Certainly got some key differentiators. I think it makes sense. We've had biologics in the space for a long time. I think physicians are comfortable with biologics. PEGylation, both of the GA drugs out there are currently PEGylated. Still unclear exactly what role that plays. Certainly is there for a very specific reason to increase the half-life in the eye. I think overall if I'm a physician and I can have less things on the drug, that's better. Great. That's wonderful. Let's go into. We're gonna spend a little bit of time on the mechanism. You know, Nora did an absolutely fantastic job walking us through the science of dry AMD as well as the mechanism of action of vonaprument and how it impacts this neurodegenerative disease. I wanna ask Ted to sort of walk us through. Much of this work has been pioneered through his lab and through his group here at the company. I wanna give him an opportunity to work through the mechanism of disease here to help us fully better understand this disease process. Ted, give us your sense. Sure. This slide shows a mechanistic understanding of how C1q is involved in neurodegeneration. It's really a foundational science of the whole company. On the left side of the slide, as Nora has already showed, you have the photoreceptors in blue. These are the cells that collect light. They send that signal up through the synaptic network up there. Underneath those cells are the RPE cells. They're epithelial cells that support the photoreceptors. As you move closer to the geographic lesion, you can see that the photoreceptor cells are becoming stressed, and this is where C1q is playing a very different role than C3 or C5. It's actually binding to the functional synapses on photoreceptor cells. This is a carryover from development where C1q is designed to eliminate excess synapses, which we want to make the strong circuits functional. In disease, it really is an aberrant elimination. When you move to zone three, synapses are gone. These cells are not functional because they can't communicate with the rest of the retina. Here, the alternative cascade comes into play a role. It recognizes dysfunctional cells. It really facilitates the removal. That's what you're seeing on the lesion edge is dysfunctional cells being removed. As they're gone, the RPE cells are gone, the lesion grows. A big distinction between C1q, which is early in the disease process, recognizing functional cells, versus C3 and C5, which are expanding the lesion edge. That's great. Thank you very much. The construct here, even though this is sort of based on the histology that we saw in a patient with GA, this construct sort of lays out the four zones of the progression of dry AMD in the early zone one and, to a large degree, zone two sort of intermediate AMD. Currently, we have very, very limited clinical options for patients that have earlier disease states prior to the development of either choroidal neovascularization or frank geographic atrophy. Nora, what do we do for patients currently with intermediate AMD? Not much. We put them on AREDS2 vitamins, and that's based on a post hoc analysis of the Age-Related Eye Disease Study 2 that show that the vitamins are basically a mix of antioxidants protect against conversion to CNV by 20%, to wet, to the wet disease. Also, I advise a Mediterranean diet because now there's quite good data from NEI on a 10-year study that that's protective across disease progression. You know, and that's just a good diet, I think, to have, and it protects the neurons as well. Right Interestingly in preventing against dementia. The only FDA-approved right now is photobiomodulation that's limited. Right use as a device. Not a lot, but we would. The other thing I would have to add to Charles's advice on what the company is doing that's so revolutionary and promising to me is intervening early I think is key. Yeah Before these synapses become dysfunctional and lost, and again, it's an irreversible loss. Yeah. Generally, what we're doing at the time of treating intermediate AMD with vitamins is trying to protect photoreceptors from oxidative stress essentially is the concept of what we're doing here. These are still functional photoreceptors. They're stressed. This is sort of zone one. That really is sort of where we're falling into, in turn, this construct of zone two, where once these stressed but functional photoreceptors are tagged for elimination, that's really sort of where the process starts, right, Ted? I mean, that's really when we start to see significant functional decline. That's a time when we can intervene as we understand it, right? Because when you think about the histology that we saw earlier on, we still see active but reduced photoreceptors over this area of intact RPE. This is a critical time to intervene. Charles, I mean, this is sort of a basic question, but photoreceptors are the key to vision, right? So we've got to protect. Do they regenerate? That's a great question in terms of these folks. I mean, you know, once we lose these photoreceptors, what happens? Yeah. It's really an overly simplistic view, but very specific regulators have said, you know, the photoreceptor is vision. I mean, put it, the most important cell in the back of the eye. That's definitely debatable, 'cause if you don't have ganglion cells, you don't see either. I mean, there are other cells that are important, but it's where vision happens. I mean, it's where light turns into the chemical and electrical signals that we think of as vision. So it is the tip of the spear. And what's fascinating about AMD, and I love this, I love this cartoon because I think it resonates with what we see clinically, is that there is a huge amount of dysfunction in these patients, even when they don't have foveal involved lesions, right? They complain bitterly about walking into dark rooms and not being able to see. You get this feeling of they are clearly impaired functionally, even if their high contrast visual acuity appears normal. You're getting broad dysfunction of the retina because a lot of the retina is probably in zone two in these eyes with geographic atrophy. We didn't get the time to go into detail, but if you look at that EZ slide I showed, right, it's 15 mm² of EZ loss, whereas it's like 7 mm² of RPE loss. You have a much larger zone of photoreceptor damage outside of the areas of GA. I like the concept of let's broaden and not just target expansion of GA, but let's actually protect the photoreceptors that are actually doing what patients want, which is see. Right. Yeah. It's critical to intervene early. You know, the idea here, this term upstream I think is important for this program because it's upstream not only in terms of the cascade, in terms of affecting the cascade early on, but it's also important in terms of upstream protection of the neurosensory retina. The other linchpin on that is the bidirectional feedback. You're targeting photoreceptors with this target, but the real hope is that by stabilizing those photoreceptors, you also then will prevent the RPE loss. Because, right, if we only protect photoreceptors and RPE still dies at the same rate, that's gonna be a problem. That's why I like that sort of second six-month data in the core data set, because when that gets borne out over 18, 24 months, that'll be really important, because you can preserve photoreceptors, which will stabilize the RPE, and then slow the growth of the underlying fundus autofluorescence pattern. Great. Well, I'd like to thank the panel, in particular Dr. Wykoff and Dr. Lad, for spending the day with us. I guess we're gonna. Open it up. We're gonna transition on to some questions from the audience. Really good discussion. We've got a microphone that's being passed around. Please, any and all questions. I see we've got some hands here, which is awesome. Hi, everyone. I'm Samantha Schaefer with Pete Stavropoulos at Cantor Fitzgerald. For Dr. Lad and Dr. Wykoff, we're curious to hear your thoughts on GA lesion size growth and whether it's a clinically meaningful indicator of disease control. More broadly, what is your sense on how community docs view this metric, and how up to speed are they? Just a follow-up question for the team afterwards. Thank you. Okay. I'll start. Geographic atrophy, I think, you know, so far historically, that's how we design our studies, and that's why the phase II study was designed with a GA, prevention of GA loss, or fundus autofluorescence as the gold standard, because that was FDA guidance at the time. And you know, that was. It's well-tailored perhaps to mechanism of actions that target the RPE, yeah, as a direct correlate. I don't know that the retina community, I think they're increasingly understanding this, and we're helping them now understanding this more and more. It is a neurodegenerative disease, and again, the RPE are support cells. They're very important, and I think they're tightly linked. We understand a lot, and I think increasingly so, but if the photoreceptors are dysfunctional, there's a lot that RPE has to clear also. I think they are synergistic, and that's why the RPE data, it lags behind. The RPE is a very sturdy cell. I do think it is an important biomarker of GA progression if it reflects the MOA or RPE MOA. This mechanism of action is a photoreceptor mechanism of action. It's a neuronal one. It's seen in other neurodegenerative diseases, as you saw. It helps patients with their, you know, preventing neuronal impairment in bad diseases. I think we need different measures. We need a functional measure and others. Yeah, I totally agree with Nora. The thing that I would layer on is that in clinical practice, we don't really use fundus autofluorescence in the way it's used in the clinical trials. We're not measuring lesions on fundus autofluorescence. OCT, you do have the opportunity to do that. We don't have the software yet in the U.S. There are some software programs that are approved in the E.U. that are being used, and I think those will be used over time in the U.S., and then we will get better at actually quantifying not only EZ, but RPE and all these different layers over time, and it will become much more relevant, because you'll be able to project this for a given patient. Right now, it's very qualitative. For Doug Love and team, building off of that, what level of effort would be needed to change physician understanding, and have you started that education process, or when do you expect to start? Yeah, we have started. Obviously, as you've heard here today, vision is what's most important from a patient perspective, but also from a physician perspective. Doing events like this, one-on-one and in group settings to assure them that we are protecting vision, and that's what matters to the patient. That's well underway. We're also doing disease education work on GA itself, which is actually really quite important. You've heard today the field for 20 years really have focused on the RPE story. More recently, with the advent of EZ and other technology, starting to look at photoreceptor neurons and their role in driving this neurodegenerative disease process. Just baseline disease education on this disease is actually really important to understand our mechanism of action and the data that we've produced. Thank you very much. Hi, good afternoon. I'm Tazeen Ahmad from Bank of America. Doug, I just wanted to ask you, have you stated what the effect size is gonna be for the ARCHER II trial? What's it powered to show? We have not, no. As Jamie said, the study is powered very highly as a phase III study. Because BCVA 15-letter loss is a meaningful, clinically meaningful endpoint, any significant protection on the BCVA 15-letter loss is deemed an acceptable or approvable endpoint. We have not stated the specific effect size. Okay. How should we be thinking about what the sham arm is gonna look like at 15 months in that primary endpoint? Yeah, it's a good question. I'll flip over to that slide, and maybe, Jamie, you wanna take that while I pull that slide out. Yeah, we used the ARCHER data set closely, and we also used the lampalizumab data set. It was a very large study, 2,000 patients for which lampalizumab did not have a significant effect, so you essentially have an entire placebo arm of 2,000 patients to look at what happens over time. Importantly, both ARCHER and the lampalizumab study both included both foveal and non-subfoveal patients enrolled. We get a good sense of the rate that we would expect. Typically, it's in the mid to upper teens per annum. You can just extend that out to approximately 15 months, add another 25% onto the rate, and that's approximately the rate we're using. Okay. Well, Jamie, maybe talk about kinda the approach we took to powering the study as it relates to the treatment and the sham group. We basically used a conservative set of estimates. I shared with you kind of a general way of getting that. We took a bit of a haircut on what we believe the rate to be. We basically overestimated or underestimated the rate of increase that you'd see in the sham group. We also took a haircut in terms of the amount of effect size that we'd anticipate seeing, from a treatment effect way. We powered the study conservatively to make sure that we stayed within the likelihood of a positive result coming out of this. Okay. Can I squeeze in- Sure. One last one? Absolutely. On looking at that 15-letter loss, the company and the doctors on stage have done a really good job of talking about the rationale for why it shouldn't be a noisy endpoint. My question is, on a relative scale, though, it's still a small number of patients that you're gonna be looking at, and how do you get comfortable that you'll be able to show the level of difference that you're looking for over this time period? Yeah. Related to that, once you look past 15 months, and maybe this is a question for the physicians as well on stage, what's your level of confidence and durability of response? Let me speak to the program first. The key component here is to have a high enough sham event rate to see a treatment effect, right? That's really key. We've designed the trial, and we monitor the trial. Well, that really is our primary sort of in-trial metric, is to do a very specific model for event rates and then see where we are as we move along. The way we have tried to maximize event rates, we've seen the numbers here, but we did employ two important strategies to support that rate if not exceed that rate. The first is we had a goal of greater than 50% foveal lesions involved, 'cause we know from the phase II study that these patients have significantly higher event rates when they have foveal disease compared to non-foveal RP atrophy. That difference was the difference between 25% and 17%, so a substantial difference. The second group that's really important to understand was in the phase II study, we included patients with very poor vision down to 25 letters. Patients between 25 letters and 45 letters in the phase II study had no events. The event rate that you see in the presentation today is based on the total cohort. We eliminated the bottom 20% that did not have events in the phase II study. Those two strategies, we believe, will have a significant impact on supporting event rates. Really, to answer your question, the key to seeing the substantial benefit is having enough event rates in a phase III study. As I mentioned, Tazeen, we are tracking events, and we're right on the money in terms of where we should be at this point in time in terms of patient months in the study. That's very reassuring in terms of the treatment effect associated with vonoprument. A question for them about durability, right? Right. Well, first I'd like to address the first one just briefly because independently we looked at natural history data, PROXIMA and lampalizumab, which basically was a large history study unfortunately. We published some work on that independent of anything we did here today with Annexon. We did find that those subfoveal lesions lost vision precipitously. They're 15 letters and more, and that's clinically meaningful. We wrote an editorial in Ophthalmology and said, "If we were to design a study, they use BCVA as a primary endpoint, we would use the subfoveal patients." I'm very pleased to see that's actually in the works here. Also, I love the stratification by BCVA because some patients, you know, you either have a ceiling or a floor, and you want to eliminate those. We see those in other clinical trials. Smart clinical trial design. Kudos to the team. Independently, we found the same thing. Clinically, durability I think is always nice to have. We do feel like once patient lost 15 letters over two visits, that's a point of no return just because it's irreversible loss, so. We'd love to see long-term data, so I know the company's committed to generating some long-term data, and we're overall pleased with the approach. Yeah, durability in these GA drugs I think is a challenge. The two points of data we have, and I'll give you my comments on them, are the phase I data which show that you have full target engagement in a month. That's good. That's great. That's very supportive. Tells you you can go at least a month. Doesn't tell you you can go two or three or four months, but it tells you you can go a month. Then we know by three months, based on that off-treatment graph, it probably has worn off because they have a three-month visit and a six-month visit on that off-treatment component of their six-month through 18 months. By three months after, it's probably worn off. You'd expect that for a small format biologic. It's gone by then. There's your range, somewhere between one and two, maybe two plus months. Who knows? It's challenging for GA drugs because there's no easy biomarker. I mean easy, E-A-S-Y, not E-Z. Like for anti-VEGFs, you got a great biomarker. It's called the OCT. You just look at the fluid. You can tell when the drug wore off because the fluid coming back. The problem with GA drugs for any GA drug, unless we come up with new biomarkers, is that you can't tell. I give you a patient, I give a shot of vonoprument to a patient, their OCT day two and day seven is gonna look exactly the same. Whereas an anti-VEGF, it totally changes. That is a key challenge for all companies developing drugs for GA. What does that mean? It means maybe we gotta come up with an AC tap or something else to judge how long a drug is gonna work for a given patient. Yeah. I think we have more questions. It's Darryl Wise, Vestech Securities. You kinda answered my question. I was curious about how rapidly decline in visual acuity was happening with patients. You kinda answered that question. Thank you so much. I gotta pivot. These are biologics which are historically difficult for manufacturing and stability. Can you talk to those two points? Yeah. We're manufacturing with Lonza, have been doing so for 10 years. The drug is quite stable. It's on their light chain path, so there's no special manufacturing tricks with regard to manufacturing. What's important about our drug is it's a Fab fragment of tanruprubart, a full length monoclonal antibody, which we've also been manufacturing for 10 years with Lonza on their light chain path. It's been really quite stable. No, no concerns or topics in and around that. Just one more point. As we look at patients' visual decline, I was curious about height and weight. Does that parlay into an understanding of the demographics of the patients, whether they're tall or short or heavy or lightweight? I'm just curious about that. We've not broken the study down in that regard. There's not data to suggest that would be a concern. The eye is actually pretty standard size no matter how tall or weighted you are. Well, I think what's important to think about with regard to our approach is we are selectively inhibiting C1q specifically in the eye, in the retina. It's a contained compartment. Your overall body weight, I would think, would have very little effect. Yeah. Is this a question about like, you gotta give more drug to big people? I mean, essentially. Yeah. That's what I thought he was asking. Yeah. The answer to that is no. The good news is we got full product engagement, and that's not an issue with these small biologics inside the eye. Even if a patient's six, seven, their eye is the same size roughly as a 5-foot person. The amount of drug that you deliver is really basically the same. The way these drugs are not metabolized in the eye. They're actually cleared from the eye. Right As a molecule, and then they're metabolized in the systemic circulation. One of the benefits of these types of small biologics that are specifically designed for use in the eye is that they're stable inside the eye, but then once they're cleared, they're rapidly metabolized. For example, we don't have to worry about vaccinations or any concern about systemic complement inhibition because the drug's gone when it gets to the bloodstream. One size fits all here. More questions. I think they're coming to you with the microphone. We need two microphones. You're gonna need a lot of drugs. Hey, Brian Balchin here from Jefferies on behalf of Andrew Tsai. Maybe a couple for management. In the event that only one sub-study is positive and the second shows trends, do you think you could still file, given FDA's new default stance? Secondly, from the blinded safety data set, can you confirm that you're still seeing zero cases of retinal vasculitis? I'll take the first, Jamie, and turn safety over to you. Yes, with regard to the first, in Europe, there's only a single study requirement, so we certainly can file there. In the U.S., obviously, if you hit on one sub-analysis and you're close on the second, you're gonna have a discussion. I think all of this is supported by what you see with the structural endpoints as well. Showing significant protection of photoreceptors via an EZ analysis would certainly be quite meaningful. We think there are multiple ways to win, and we've prepared multiple scenarios for that. Then just with regard to safety. We've seen no cases of occlusive vasculitis at all. Hi, this is Ananda Ghosh from Wainwright. A couple of questions on the trial design and then one general question. You know, one of the questions we keep getting is regarding the confidence interval that you have seen in terms of the risk reduction of vision loss in the phase II, and how it got implemented in the phase III trial design, and then I have like two more follow-up. That's the Kaplan-Meier curve. He's talking about. We powered the study based on the proportional analysis and not the Kaplan-Meier. We'll do this analysis, but the study was powered based on the proportion of patients who experience a 15-letter event. Just a proportional analysis versus the two groups. In this, you'll notice, do you have the Kaplan-Meier up? Yeah. We don't. You could see the confidence intervals were quite high. You can see the 0.09-0.8. We have a very strong confidence interval. Remember, the phase III study is almost three times the size of this, plus two to one active. The study is very well powered for this analysis as well. Probably one question you might always get is, like, how is the trial kind of differentiated from lampalizumab trial, Roche's? It's- First, mechanistically. Yeah. It's very different mechanistically. You know, this is a completely different program. The second piece is that, it's similar in terms of taking both subfoveal and non-subfoveal patients, but in the lampalizumab study, they actually included patients with vision down to 25 letters. Mm-hmm. They had a lot of very poor vision patients. Again, mechanistically, it's apples and oranges really. Got it. Can I have the last question on, you know, there's this issue of like, how do you control the eccentric fixation when you are measuring, like the BCVA or like? Yeah. It's actually not specifically controlled because the patients are able to sort of tilt their head or look askew slightly to try and find the best point. They're actually encouraged to be able to find a focal point that they're able to resolve as best as they can. You know, they're put in the machine that we all know about to be able to correct their vision. That's why it's called BCVA, so that you fully correct vision as best as you can. You give patients every benefit of the doubt to try and get the best vision that they can. I don't know, probably Charles Wykoff and- Well, I was gonna bring up the case here, which it kinda speaks to your question about eccentric fixation. You see, you know, green is good, black is bad. So the answer to your question here is at month 12, this patient is desperately seeking to eccentrically fixate, and that's in fact why they've lost vision. You know, they don't have really intact ellipsoid zone until well outside the fovea, and you've got these tiny little islands in the foveolae back. So this is in essence why these patients are likely eccentrically fixating to some degree, even at presentation. They are searching. That's the whole point of these patients with foveal disease is that they're right on the cusp of consistent clinically meaningful vision loss. You know, at baseline, you would, you could imagine that this patient is doing some degree of searching with eccentric fixation. By month 12, you know, it's a much more dramatic effect. But we don't. Clinically, you're not really able to evaluate that with protocol vision. Is that fair, Charles? Yeah. I agree with that. You actually see this constantly in GA patients. Yeah. They don't look right at you. They look at your ear. They look at the side of your shoulder to see your face. They're constantly changing geographically what part of the retina they're using. Once the fovea is involved, even if it's just a tiny involvement, even less than the left picture here, like, they'll start doing that, and you can see that on microperimetry. Microperimetry is essentially checking vision across 60 or 100 spots at the back of the eye, depending on your pattern, and you can see where they fixate, and it will migrate around. A patient can stay at 20/20, for example, and yet use different photoreceptors depending where they are. That's unusual, but that that's why high contrast visual acuity is such a challenge for many of their programs. Thanks. Hi. Bill Maughan, Clear Street. Two for me. First of all, for the practicing physicians, what would you expect for patient compliance for a monthly injection? Then for the company, with the new default stance being one study for approval, is there the possibility of changing the analysis plan and simply looking at this as one large study and helping your statistical powering? I'll start with the first one. Patients are desperate for something that slows down this disease. I can tell you that they don't mind coming in monthly. This is absolutely no problem. As long as they get visual protection, they'll have no issues coming. I could tell you that. You know, the currently approved drugs have a flexible dosing interval, and they have the real motive. Even if they know that it's less protective than what's proposed here, they'll still come in every month because they're so motivated to not lose vision. I don't think that's much of an issue. Charles, what do you think? Agree completely. Yeah. Yeah. Just with regard to the single study, we will have the discussion with the regulators. Again, we're well overpowered for a single protocol analysis. We saw the Dr. McGarry, communication through the New England Journal of Medicine, which is an interesting way to communicate a regulatory guidance. Be that as it may, we will have the discussion with him. For us, that's upside on the program. Good. That's how we view it. Thank you. Hi, this is Joyce Zhou on behalf of Anupam Rama, JP Morgan. First, for the physicians, assuming the phase three hits its win scenario, what profile of patient would make a great initial candidate for this drug given the vision preservation benefit? Would it be patients at highest risk of vision loss? One for the team. Could you remind us if ARCHER II succeeds, what your plans are for developing a pre-filled syringe? Thank you. Right. I'm happy to take that first. You know, I think it depends on the drug. I explain what I mean by that. An anti-VEGF, right? If you have a patient with new wet AMD, they're gonna 99.9% of those are gonna get treated because the drugs work. They work really well at protecting vision over time. In GA, it's a much more complicated scenario right now commercially. There's a lot of doctors and patients sitting on the sidelines not getting treated because of this thought of a risk-benefit ratio and also a question mark of efficacy, and you've heard that debate played out 1,000 times on podium over the last three years. That's why there's a lot of GA patients not getting treated. If we had a drug that just, say, a perfect scenario, improved vision in GA, reversed the lesion growth, everybody would use it, every patient. It depends on the drug, right? In this case, if this drug bears out and shows exactly in phase III what it did in phase II, I think you're gonna see a lot more patients getting treated a lot more consistently because patients don't like to lose vision, and they tell us that every single day, whether they're on treatment with current drugs or not. I agree. Again, these patients are motivated, and even if they have good vision, if they lost one eye already, it's a no-brainer. Those are the easiest patients to treat, and they'll be the most motivated by, I think, everybody. The whole idea here is to intervene as early as possible before those synapses are dysfunctional and lost. I think patients will understand that. The clinical data is so good, and if the vision will be protected and the risk profile, the side effect profile is so great, no C3-increased CNV effects, no vasculitis. I think it's a very easy conversation to have, and honestly, I will treat everybody or offer the treatment to everybody, and the data will speak for themselves at that point. Great. In terms of the pre-filled syringe specifically, sort of lifecycle management generally, work's already underway in terms of a pre-filled syringe. We all recognize the value of a pre-filled syringe. There's tremendous efficiencies that are offered to clinical practice. There's also safety issues that are very important as well. That work is already underway. The other comment I'd make about lifecycle management generally is that, you know, as a small volume drug, we have a good bit of flexibility in terms of how we manage longer duration of action. You know, there's certainly more volume as an option. Alternative pathways extend the lifespan of drug in the eye with different types of extended release platforms. One of the nice things about our formulation as it stands today is it gives us a good bit of flexibility in terms of lifecycle management going forward. Good question. Hi, Joseph Stringer with Needham & Company. Just wanted to follow up on some commentary that you had earlier on the impact of the patients with BCVA less than 45-letter. Maybe just expand a little bit more on the expected impact of excluding those patients in the phase III. In the phase II, if you excluded those patients that had less than 45, what does the treatment effect look like? And then a second question on EZ loss. What does EMA need to see on the relationship between the EZ loss and BCVA? Is it as simple as hitting stat sig on both of those, or would you need to show more or additional correlation between those? Maybe Jamie, you wanna take the first. Yeah. In the first case, what we did. Again, we haven't shared these data publicly previously. If you take the same criteria which we applied to phase III and apply that to the phase II study, we see an improvement in terms of the effect size. Because if you eliminated, as already pointed out, as Lloyd pointed out, almost 20-ish, a little more than 20% of the patients had a baseline BCVA below 45. If you take those out of the denominator, your effect size goes way up in the sham and the treatment effect just gets greater. It's quite a positive. We took the ARCHER II data as it is, and that's how we powered the phase III study. The phase III power goes up. Yeah, that's correct. Look, we're a conservative company, so we just haven't shown that analysis. We could do it, but we've got to demonstrate it in the phase III. Just as it relates to the EMA, the requirement is just to win on the BCVA 15-letter loss. We of course wanna support it with structural data. I think it's important for the treating physicians and the community alike, but for the approvable endpoint, it's BCVA 15-letter loss. Thanks. Any additional questions? Oh, I think we got another one in the back. Yeah. Just a question of pricing. Well, I think we gotta use the microphone on that. Yeah, there you go. Okay. It's Darryl Wise again, Vestech Securities. A great panel. Thank you guys for your candor. Curiosity on the GA platform. You mentioned that maybe as patients lose vision, they will be eager to be able to take on this new therapeutic. I was just curious, at what price? Has anyone talked about pricing at this current level? Yeah, we're certainly doing the work now. The pricing that's in place for the currently approved therapies would probably be the floor. We think this is a potential superior premium opportunity. What that is needs to make sense. At the end of the day, our core mission is to serve the patient population. We will not price this in an outsized way, but we wanna make sure we get value for the product that we're bringing forward. Awesome. Great. Any other questions for anyone else? All right. Well, listen, that brings us to a close, today. Hope this has been helpful for you all. As you can tell from the company as well as from the expert panel, we're really excited about this opportunity. vonoprument is a differentiated asset, both from a mechanistic perspective, which translates to unique outcomes from a structural and functional perspective, but also we think the drug candidate itself has the potential to be differentiated on the safety side. So a really unique benefit risk profile to change the lives of millions of patients worldwide with regard to that. It's a large market, and we again, will come back on the market. We've heard various discussions about is this truly a market based on sales today? Not a good barometer. I think if anything, what I would do is look at what sales were in the first nine months or so when Syfovre was launched. It was a hockey stick. We think we can do that and more, and so we're excited by that. I can't see this slide anymore. The phase III study is really thoughtful, as you all can see. We took a lot of time in really mining what is the first vision-sparing significant data set with ARCHER, but we didn't stop there. We looked at all of the other GA programs, importantly lampalizumab, probably the best learning study that's been conducted in the space. We're really encouraged in the way that we thought through the patient population and the design of the study to give us the greatest opportunity to succeed. I'm happy to report that the regulators are in agreement with this. This is the only phase III program that has full regulatory alignment on both continents in the U.S. and Europe, and we've got all the designations to go with it. It's a very warm relationship with them. They're pulling for us, and they're working with us. When we wanna meet with them, we meet with them in person. We really like that. That's really unique in today's regulatory environment. We're beginning to prepare for the opportunity from a commercial perspective. If you think about what's occurred predominantly in the wet AMD space as well as in the GA space, these have been smaller biotechs at the time they've launched. That's because there's what? 3,000 or so retina specialists with a few large practices predominantly driving the opportunity here. We can do this ourselves. We're preparing to do this ourselves. We're excited by the opportunity to bring this drug forward to patients worldwide. We appreciate you all's support and wanna thank our panel once again. Certainly Dr. Lad and Dr. Wykoff for coming out. It's a cold day in New York, but we're happy to be here. Thank all of you all once again. We will have refreshments in the room next door for a small reception. Come join us there. Be happy to talk to you one-on-one. Thanks a lot.