Morning, and thank you for joining us to discuss 24-month data from the DERBY and OAKS phase 3 studies evaluating pegcetacoplan in patients with geographic atrophy, or GA. For those participating via conference call, we have made the slides available via webcast. A replay of this call will also be available on our website following the call. Before we begin, I would like to point out that we will be making forward-looking statements that are based on our current expectations and beliefs. These statements are subject to certain risks and uncertainties, and our actual results may differ materially. I encourage you to consult the risk factors discussed in our SEC filings for additional detail. On today's call, I am joined by our Chief Executive Officer, Dr. Cedric Francois, our Chief Medical Officer, Dr. Federico Grossi, and Dr. Eleonora Lad, Associate Professor of Ophthalmology and Director of Ophthalmology Clinical Research Unit at Duke University Medical Center and Lead Principal Investigator for the OAKS study. Adam Townsend, our Chief Commercial Officer, will also join us for the Q&A session. Timothy Sullivan, our Chief Financial Officer, is unable to join today due to travel conflicts. Now I'll turn the call over to Cedric. Thank you, Meredith, and good morning, everyone. Today marks another important milestone for us at Apellis as we seek to bring the first-ever treatment to patients living with geographic atrophy, or GA. On this call, we will be reviewing the 24-month results from our phase III DERBY and OAKS studies evaluating pegcetacoplan, our targeted C3 therapy for the treatment of GA secondary to age-related macular degeneration or AMD. Today we'll review the data in more detail momentarily, and we are fortunate to have Dr. Nora Lad here today to share her perspectives. First, let me provide a few introductory comments. GA leads to the destruction of the retina and irreversible blindness, and we are thrilled with what these 24-month results could mean for patients. Building on our previous data, the 24-month data showed that treatment with pegcetacoplan resulted in increasing effects over time. Specifically, between month 18 and 24 in the combined studies, we saw an acceleration of the treatment effect of pegcetacoplan, reducing GA lesion growth by 30% and 24% in the monthly and every other month arms, respectively. Put simply, the longer patients were treated, the better they responded to the drug. For a drug to demonstrate not just durable, but increasing effects over the study period is incredibly rare. This means that patients with GA could save more and more of their photoreceptor cells each year, resulting in substantial slowing of their GA lesion growth and the potential to preserve their vision for longer. Importantly, we also continued to see a favorable safety profile in line with what we saw at 12 and 18 months. There were no new serious adverse events of ischemic optic neuropathy or new cases of endophthalmitis between 18 and 24 months. New-onset exudations were consistent with longer term exposure. The key secondary functional endpoints were also assessed at 24 months. As expected, there were no clinically meaningful differences observed. As we have mentioned before, and as you'll see in the data, we believe this is due to the challenges with measuring functional vision in GA patients, as well as the relatively short period of time over which they were assessed. We anticipate a separation to occur over longer periods of time. The 24-month results will serve as the basis for our European application for pegcetacoplan, which is on track for submission by the end of this year. In the U.S., we are looking forward to the upcoming PDUFA date of November 26. If approved, pegcetacoplan will be the first and only treatment available for patients with GA, setting a new standard for GA moving forward and providing Apellis with the opportunity to establish the market where nothing has existed previously. The potential product profile for pegcetacoplan is compelling, including, first, robust efficacy and safety data in more than 1,200 patients over 24 months. Second, flexible dosing options with both monthly and every other month treatments. Finally, increasing and clinically meaningful effects across a broad, highly representative patient population, including both extrafoveal and foveal lesions. In fact, between months 18 and 24, foveal lesion growth reductions were comparable to reductions in extrafoveal lesions in the combined studies. More than ever, we believe pegcetacoplan represents a breakthrough for patients globally who are living with GA. We look forward to sharing more detailed data at upcoming medical meetings, including at the American Academy of Ophthalmology next month. Let me now turn the call over to Federico Grossi to walk through the data. Thanks, Cedric. Before we review the data, let me first quickly remind you of the study design. DERBY and OAKS are double-masked, randomized controlled global phase III studies comparing the efficacy and safety of monthly and every other month intravitreal pegcetacoplan with sham treatment in more than 1,200 GA patients across more than 200 sites worldwide. worldwide. The primary efficacy endpoint of both studies was the reduction in growth of GA lesions as assessed by fundus autofluorescence. The studies continue for a total of 24 months, with patients remaining in the randomized masked treatment groups. In addition to our earlier 18-month analysis, lesion growth was assessed at month 24 as a pre-specified secondary endpoint, and key secondary functional endpoints were also assessed. Let me now review the data. I will start with the effects of pegcetacoplan at the six-month intervals. These are the most important data in this analysis as they show how the treatment benefit evolves over time. As we know, GA is not a one-year disease, so it's critically important to understand the effect of pegcetacoplan at various time points over the full 24 months. Particularly, the last 6 months interval is important because the treatment effect during this period tells us about how the treatment is benefiting patients today and what we can expect as the base benefit moving forward. As you can see on this slide, treatment with pegcetacoplan resulted in increasing effects over time in both DERBY and OAKS, with an acceleration in the reduction in lesion growth, specifically between month 18 and 24 as compared to previous periods. This increase in effects becomes even more clear when looking at the combined data from DERBY and OAKS, as shown on this slide. With rate between months 18 and 24 increasing to 30% and 24% with monthly and every other month treatment respectively. The potential magnitude of the benefit to patients could be substantial. If this increasing effects continue, it could mean that the curves for the treatment arms have the potential to flatten over time. The acceleration in months 18-24 was driven by slower rates of lesion growth in the pegcetacoplan treatment arms and not by faster growth rates in the sham arm. Sham was linear for the duration of the studies, with highly consistent growth rates of approximately one square millimeter per six months over each of the four 6-month intervals. When we look at the effects in both extrafoveal and foveal lesions within this 18-24 month period, we find that pegcetacoplan appears to be equally effective across both extrafoveal and foveal lesions, not only in the monthly treatment arm, but also in the every other month treatment arm. These are very encouraging results, further underscoring that pegcetacoplan works in a broad patient population regardless of lesion location and reinforces the importance of early and consistent treatment. We will share more detailed extrafoveal and foveal data at an upcoming congress. The increased effects over the 24-month period was also translated into greater reductions in lesion growth from baseline out to month 24, with all nominal p-values less than or equal to 0.003. What is more striking about this graph is the treatment curves for both DERBY and OAKS. We now have two independent studies that are behaving similar in terms of overall effect size at 24 months in the monthly arm as well in the every other month arms. In DERBY, treatment with pegcetacoplan resulted in a 19% and a 16% reduction in lesion growth in the monthly and every other month arms respectively. In OAKS, there was a 22% and an 18% reduction in lesion growth with monthly and every other month treatment respectively. This mean that a growing amount of retina tissue is being preserved across both studies over the 24-month period. If this effect continue over longer periods of time, the amount of retina saved could have a substantial impact for patients. As part of this analysis, we also assessed the key secondary functional endpoints. Because two years is a relatively short time to assess functional benefits, as expected, there was no clinically meaningful or statistically significant difference between pegcetacoplan and sham at 24 months on the key secondary visual function endpoints. Today, I will summarize the best-corrected visual acuity (BCVA) results from the combined studies. More on functional endpoints will be presented at an upcoming congress. As you can see, there's variability across all three arms over the 24-month period. The monthly and every other month treatment arms perform relatively in line with sham at various time points, with sham bouncing back in month 22 and 24. This variability further underscores that one single time point may not be adequate to evaluate functional benefit in GA due to the high variability. Due to this change in the last two months, we observed a loss of one letter in the monthly arm and less than two letters in the every other month arm at 24 months as compared to sham. This difference is not clinically meaningful. We believe we'll see a benefit over longer periods of time as the reduction in lesion growth translates into visual function. We look forward to following our GALE extension study, where patients are treated with pegcetacoplan for an additional three years. Turning to safety. Pegcetacoplan continues to demonstrate a favorable safety profile consistent with safety data reported today and longer-term exposure to intravitreal injections. The combined rate of new-onset exudations over 24 months was 11.9%, 6.7%, and 3.1% in the pegcetacoplan monthly, every other month, and sham groups respectively. No cases of endophthalmitis were reported between month 18 and 24. Over the 24 months, the rate of infectious endophthalmitis was 0.034% per injection, and the rate of intraocular inflammation was 0.24% per injection. Both of which appear to be generally in line with reported rates in studies of other IVT therapies. Additionally, no serious adverse events of ischemic optic neuropathy were reported between month 18 and 24, and no events of occlusive vasculitis or retinitis were observed across the entirety of both studies. With that, I will now turn the call over to Dr. Lad. Thanks, Fede, and good morning, everyone. I am pleased to join the Apellis team today to share the full 24 months results from the DERBY and OAKS studies. This is an important readout for the retina community, providing us with even more data around the effect of pegcetacoplan in geographic atrophy. GA is a devastating disease that causes patients to lose more and more of their vision every year, resulting in irreversible blindness. Patients with GA lose their independence, and they can no longer take on tasks which are crucial in their daily lives. The results shared today are remarkable and give these patients hope. It is rare for drugs to show increased effects over the study period, yet this is what we're observing with pegcetacoplan and its ability to slow down the progression of GA. It is fascinating to think what may be possible with even longer treatment. When looking at the 24 months data in the DERBY and OAKS studies side by side, a few things really stand out to me. First, despite the variability that characterizes geographic atrophy, the sham control arms are virtually identical and linear in both studies. Consistent with previous large studies in GA, most notably the lampalizumab CHROMA and SPECTRI. This means that these results were clearly driven by pegcetacoplan and not by an inconsistent sham. Second, the efficacy and safety profile for pegcetacoplan were robust across both the monthly and every other month dosing, and in both extrafoveal and foveal lesions. While we would like to have seen an impact on visual function, this did not come as a surprise. Given the increasing rate of lesion size reduction, we can expect to start seeing functional impacts emerge over the next two years. Finally, based on these data, and should the increasing effects continue beyond year two, it's now possible to believe that treatment with pegcetacoplan may ultimately halt the progression of the disease over several years of treatment. Now, I'd like to turn the call back over to Cedric for his closing remarks. Thank you, Dr. Lad. In summary, pegcetacoplan's transformative potential in GA is further reinforced by the 24-month data, demonstrating the potentially increased benefit for the millions of people with GA who are at risk for vision loss with no treatment options. DERBY and OAKS are some of the most comprehensive and meaningful studies in this business. We have a potential treatment that we believe is increasingly effective, with a favorable safety profile and multiple dosing options. All of us at Apellis remain committed to bringing pegcetacoplan to GA patients, eagerly awaiting the FDA decision in November of this year and advancing our ambition to be number one in the retina. I would like to close by again expressing my sincere gratitude to patients, physicians, and site staffs participating in the DERBY and OAKS studies. It is thanks to all of you that this milestone was made possible. To our amazing team at Apellis, we are so grateful for your unwavering commitment to advancing care for people living with GA and other complement-driven diseases. With that, operator, please open the call for questions. If you'd like to ask a question at this time, please press star one one on your telephone. Please stand by while we compile the Q&A roster. Our first question comes from the line of Jonathan Miller with Evercore ISI. Your line is now open. Hey, guys. Thanks so much for taking my question and congrats on the update. It looks very interesting. I have a couple of little questions. First, on the regulatory front, you mentioned the 24-month data being the basis submission from the E.U., but you didn't talk about whether you're gonna submit that to the FDA and what your expectations are for their response to the availability of this data, if any, on the PDUFA date. Secondly, maybe more housekeeping. Can you explain some of the numerical changes to the data since the 18-month update? It looks like a couple of bars have shifted around by 1% or 2%. Likewise, the every other month arm, when you say it has 28% efficacy in both foveal and extrafoveal patients, but then on slide eight, it's only 24%. I just wanna get a sense for where those minor discrepancies are coming from. Thank you so much, John. First of all, for the first question with the FDA. When we submitted the 18-month data to the FDA, we also included of course, whatever we had available beyond 18 months. In many ways, this is basically a confirmation of what we suspected already at 18 months and which is now confirmed. For the FDA, there will be no major amendments, and we will simply provide them with the update as we have to you. For the numerical changes. When you do the modeling with the MMRM, and the way in which the data are when you recalculate it, there can be these small changes. I mean, they're not meaningful, but it's depending on how the model goes through the different segments of the time point. That's really what it is. Okay. Makes sense. Maybe on the functional side, are there any other functional signals that might be better than BCVA for getting some sense of a functional benefit at an earlier time point? Is there any visible effect on like PROs or anything like that that we could expect to see at AAO? Thank you, John. At this point in time, after two years, we don't really have anything yet on the functional endpoint that pans out. You know, we will talk more about functional endpoints at AAO and later as well as we do more analyses. The key thing is that with what we see with this increased effect over time, what is really tantalizing is the possibility that this disease ultimately may slow down completely, right, in many of these patients. That will inevitably result in functional changes, we believe, and that's something that we will also be able to evaluate, of course, in GALE. At this point, you know, this is the endpoint, if you want, for the DERBY and OAKS studies, and that we couldn't be more pleased with the results. Yeah. Thanks so much and congrats again. Thank you, John. Our next question comes from the line of Madhu Kumar with Goldman Sachs. Your line is now open. Thank you. This is Omari on for Madhu. We have a few questions. First, given these data, how should we think about the GALE OLE, particularly patient retention? What gives you confidence based on prior EMA interactions, the functional data, to support a year care goal? I'll ask the last question after those. Thank you so much. Well, I will hand the first question over to Nora, who's actually Dr. Lad, was an investigator in DERBY and OAKS and has also enrolled patients in GALE. Nora, would you like to comment here? Certainly. I'm delighted to be here. The patient experience has been very positive with this. Unlike other prior studies, the retention in GALE, the extension study, has been excellent. I understand 85% as a whole. At our particular site, it was 100%. I'll tell you a few anecdotes from some of my patients. Keep in mind, these are elderly individuals with comorbidities during a pandemic. They had a hard time, you know, continuing the visits. They said, "I think Dr. Lad, I'm done with this study." Then one of them especially went to an optometrist and got their prescription checked, and the non-study eye deteriorated substantially, whereas the fellow eye stayed stable. He came back and said, "Dr. Lad, I take this back. I need to stay in this extension." Then there are others with similar subjective and objective experiences. Everybody was retained, which is pretty remarkable, I think, in telling. Also, the retention in OAKS and DERBY was great, and I think similar only and in line with anti-VEGF studies. Thank you so much, Dr. Lad. For the EMEA submission. As we've always mentioned, the 24-month data will be included in the submission, which is scheduled to happen before the end of the year. That submission, you know, or the request from the EMEA is to understand the relationship between the functional endpoints and the lesion sizes, right? To have an idea what it means over the longer term, meaning beyond two years, for the function of these patients. It is important to note that the variability on the functional endpoints and the fact that we really have no good way of measuring visual function is the reason why at two years it is too early to really be able to see that with the lesion size reduction, because remember what we measure is dying photoreceptor cells, right? That should naturally translate into functional benefits over a longer period of time. So. For our last question for Dr. Lad. Given this 24-month profile for PEG, what kind of GA patients would you think are best suited for this drug? And what would you need to see from competing agents to select them over PEG? That's an excellent question. Thank you. I have a hierarchy in my mind already, but these data actually make my conclusion even stronger. Who to treat? I think all patients will benefit to prevent loss of retinal tissue according to these data and to prevent new areas of blind spots, which would decrease peripheral vision as well as deepening their central vision loss. My number one choice remains the patients that lost vision in the other eye. In any GA in the study, I would or, you know, the treated eye. Now, if both eyes have useful vision, I would recommend still that the patients that are extrafoveal are treated next to prevent the foveal involvement, because this is the most valuable real estate that we have in the retina responsible for central vision. Number three would be foveal GA patients, because I think they still benefit long-term. Visual function, it is difficult in GA to assess in a two-year interval. We need long-term data. Over time, we'll prevent enlargement of their blind spot, loss of their peripheral vision, pericentral and then peripheral, and decreased central vision in the long term. I would treat everybody in that order. The data is getting better and better and gives me more hope and optimism as a retina clinician and for my patients. Could you let us know what would you like to see from competing agents to select them over peg? I'm sorry. Can you repeat that for me? Sure. What would you need to see from competing agents to select them over peg? Yes. I think I probably would like to be able to classify patients in terms of lesion characteristics to see who are best candidates for a particular drug. That's what I do currently with anti-VEGF agents, and we have a few tools in our armamentarium. We used individualized imaging to guide treatment decisions. I'd have to see more data from the competitors right now to draw conclusions, but I can tell you right now, all GA will be a good candidate for pegcetacoplan. Then down the road, I'll probably refine my treatment according to, the profile that I see from competitors as well. Thank you for taking our questions. Our next question comes from the line of Anupam Rama with J.P. Morgan. Your line is now open. Hey, guys. Thanks so much for taking the question. Just a couple of quick ones from me. At the AAO presentation, what new analyses will we be getting? Second question, Cedric, I think what we're trying to understand here, and I've gotten a couple inbounds on this, is around the visual acuity data, and if there is any regulatory risk based on what we know today around the E.U. filing based on visual acuity data. I guess final question, Dr. Lad, how do you think about every other month dosing? And does that matter to you as a potential, you know, optionality for pegcetacoplan? Thanks so much. Thank you, Anupam, and good to hear you. Start with the first two questions, and then I hand it over to Dr. Lad. At AAO, you know, the new analyses. You know, we are running the analysis, so we're going to run the analysis still. We'll see what we will be able to present at that point in time. It will be in line with, you know, our history over the past year of providing very good insight into the data that we have. The VA data and the regulatory risk in Europe, to go back to the question that I got from John, we believe that this case further strengthens our submission with the European Union. I'd say when you look at DERBY and OAKS next to each other at 24 months, and when you consider these increased effects over time, and how similar after 24 months DERBY and OAKS have become, it's very hard to imagine. Remember, you're measuring dying photoreceptor cells, right, with a sham that is absolutely exquisite. It is very hard to imagine this drug not getting approved. I have no doubt that we'll be able to build a story around the functional lesion size correlations. Dr. Lad, would you like to continue on the question? Sure, definitely. First I'd like to finish up on the UI. I think it's great that the 24-month data will be submitted there. I think our tools has also improved on the key secondary endpoint to have the data as they are, and it came to. It's no surprise to us. However, our technology has improved on structure function correlation in terms of algorithms and ways to look in more detail at this disease. I think this will all help. Longitudinal data will be critical, as was mentioned a few times now, and very important in this disease. I think we'll have that, and that will decrease the risk of the E.U. submission. In regards to the last question, also very important for our patients, how often do you treat? First of all, today's data suggests the long-term treatment is beneficial to achieve a maximum benefit in preventing degeneration. Maximum benefit is overall with monthly, and consistently with the data. Every other month really seems to give the patients, according to these results, 80%-90% of the effect, depending on what time point group you analyze in both studies. It's also a very good option, very valuable in patients that will be unable to return for monthly treatment. As a clinician, we know down the road that sustained delivery will be beneficial, that's down the road, and that will be next step for any approved intravitreal drug for GA. Our next- Thank you, Anupam. Our next question comes from the line of Tazeen Ahmad with Bank of America. Your line is now open. Hi, guys. Good morning and congrats on the good updated data. Couple of questions from me. Cedric, did you specifically submit the visual acuity data when you provided the 18-month and beyond update to FDA? Secondly, can you just remind us when the mid-cycle review meeting with FDA will be? Is that gonna be a live meeting, or is it just going to be written commentary that you exchanged with the agency? I'll have one question for Dr. Lad, if I could. The VA data was included with the 18-month submission and as well beyond. All the data that we had available at the time was part of the package. Again, that will not be a surprise at all. For the mid-cycle review, we're not gonna comment on that, you know, but we feel, of course, very good about that interaction. You know, we haven't had it yet, but and we're not commenting on exactly when we will have it. Dr. Lad, as it relates to the specific data of, I think it was one letter loss in the every month arm versus just under two letters in the every other month arm. To follow up maybe on Anupam's question about your view of every month and every other month. Taking that data into account, would you feel, you know, as comfortable dosing every other month as you do every month? I think monthly is better. Overall data from studies that show that the maximum benefit is with monthly treatment consistently. We have a similar scenario with anti-VEGF. There's under-treatment in the community. Still, the best results are done with frequent treatment per everybody's individual disease. However, keep in mind, I think visual acuity data right now is very difficult to gauge after only two years. It's a nonlinear function, unlike lesion growth in GA. It's difficult because the vision stays stable for extrafoveal lesions until foveal involvement, and then it decreases slowly over time. We will see more in GALE, I think longitudinally. Right now, the one to two letters, I would not make too much of these data right now because it is too early to gauge. I would still make the same recommendations based on prevention of lesion growth and the retinal degeneration with pegcetacoplan. Because we know with increased GA size, the blind spot, which is scotoma enlarges, and that could be central peripheral, and it really affects their activities of daily living for our patients. The prevention is GA growth, and I would still make the same recommendations based on the data. Do you think that based on what you just said, there should be meaningful difference, depending on what part of the complement cascade one is using, whether it's C1q or C3 or C5, as it relates to the impact on visual acuity and time to impact? That's an excellent, very insightful question. I don't know yet, but I'll tell you after these data. I've done quite a bit of reading on immune senescence, immunomodulation, and different aspects of the complement cascade, the MAC effect function and how. I've been working on visual function for 10, 11 years now or more in dry AMD, and I think there's a lot to learn. Time will tell, but that's a great question, and I'll take it back to the lab and start to think about how to best address. Okay. We'll look forward to the update. Thank you. Thank you so much, Nora. I think it's maybe one little clarification there as well for people that may not be that familiar with it. Visual acuity is really a measurement of central vision alone, right? It is one spot in the retina centrally, whereas the periphery is not measured in visual acuity. If somebody can have significant geographic atrophy affecting the periphery meaningfully in a highly functionally impeding way, and when that person reads Snellen charts, that person will still have 20/20 or 20/40 vision. That entirely happens very often. That's why visual acuity is a poor measure in geographic atrophy, because it typically starts outside of the fovea and then at the end only starts overtaking the fovea, at which point it will affect visual acuity. That's correct. Our next question comes from the line of Colleen Kusy with Baird. Your line is now open. Hi. Good morning. Thanks for taking our questions, and congrats on the updates today. One on safety, if I could. The non-exudative CNV events come up in some of my conversations and, obviously there's another competitor in this space. Can you just remind us, are non-exudative CNV events being measured in DERBY and OAKS? Kinda how would those patients be managed and what your thoughts are on what that non-exudative signal might mean? Yeah. Thank you so much, Colleen. Well, I will briefly comment on how we measure these lesions, and then I will let Dr. Lad comment as well. First of all, I think this is really, really important, non-exudative CNV does not get treated with anti-VEGF, right? I think that is really important. It is also really important to mention that you can measure CNV at the time of an exudative event. Basically, the patient comes in, there is liquid in the retina, and you want to treat that patient with anti-VEGF, which is an exudative period. After the patient is then on anti-VEGF treatment, if you look at 1 year or at the end of the study, then of course those lesions will be dry and you could say they're non-exudative, but that is because they are on treatment with anti-VEGF. Typically, the way it happens in our protocol is that every patient who has exudation gets treated with anti-VEGF and goes on standard therapy until the end of DERBY and OAKS. That, I think, is really important. There's not a single patient in this study that was detected with exudative lesions that was not treated with anti-VEGF. We only had two cases outside of that, for other things that were treated with anti-VEGF, but it's the complete picture. Dr. Lad, I don't know if you would like to comment on that as well. I think you covered it really well, and I don't have a lot to add other than I treat exudative CNV in my clinic, not the non-exudative disease with anti-VEGF. That's helpful. Thank you. Thank you. As a follow-up, in the GALE study, can you just confirm, are you measuring visual acuity there? Based on the data you've seen so far for DERBY and OAKS, do you have a sense on how much follow-up you might need to see separation in terms of those functional endpoints? Yeah. We haven't run these analyses yet, but we of course are measuring visual acuity. We will also continue to measure lesion size growth, not as frequently as we did in DERBY and OAKS, so this will be every six months update. We also continue to do microperimetry in the patients that continues out of OAKS into GALE. It's gonna be very comprehensive. It is approximately 800 patients that we'll be able to follow for the next three years. Great. Last one. For the 24-month update for DERBY and OAKS, did you look at visual acuity based on the foveal versus extrafoveal subset of patients? Did you see similar trends or anything different in those populations? That is still being subjected to further analysis, but so far, we don't see differences. Great. Thanks for taking our question. Thank you. Our next question comes from the line of Layla Youssef with Cowen. Your line is now open. Hi. Thanks so much for taking the question, and congrats on the progress. Maybe really quickly, could you elaborate on what drove the acceleration that you saw in the reduction in lesion size for, I think it's the six months between 18 and 24? Specifically in the DERBY trial, it seemed like there was a jump there. I have a follow-up question for safety for Dr. Lad. Yeah. Thank you, Laysa. This is something that is incredibly exciting to us, right? I mean, it is worth noting, we don't see it in DERBY and not in OAKS. Remember, in every other month in OAKS, we see it as well. It is only in the monthly arm in OAKS, where we also see a compounding effect, so an acceleration, but it is smaller than in the other arms. That was the arm that performed the best at the start of the study as well, of course. It's important to note also that when you look at the area of retina saved, this continues to happen. I mean, in DERBY, in the second year, there is twice as much retina saved as was the case in the first year. It makes a really tremendous difference for these patients. As it relates to the mechanism behind it and what could be going on, look, at the end of the day, and this is something that we've postulated from the very beginning, is that when you control complement over a long period of time, we believe that you make an adjustment in the immune microenvironment that drives this disease. Geographic atrophy, we believe, is similar to climate change, right? A homeostatic system that goes out of control. For a homeostatic system, for a retina to be healthy, there are many buffering systems that keep that retina in a healthy state. There needs to be a tipping point after which the disease occurs. At that point in time, the same buffering mechanisms will keep that pathological state in a very tenacious spot. In order to come back, you probably have to work up against that same tipping point and then get over to the other side. Which is why, again, we are, you know, really intrigued by the possibility that ultimately, over several years of treatment, this disease could be stopped, growing altogether. Gotcha. That's very helpful. Maybe for Dr. Lad, could you maybe go over maybe in a little more detail your impression of the current safety profile, maybe specifically the actual, the rate of the new onset exudations? I've seen a little bit of an increase in the monthly arm with the update. While there hasn't been any new cases of ION, you know, there were some previously. You know, how are you thinking about maybe those elements of the safety profile in your mind, as you think about pegcetacoplan? Thank you. Thanks. Thank you for the question. I think the safety profile is quite favorable. Again, there have been no additional cases of endophthalmitis between months 18 and 24. The rate over 24 months is low, 0.034% per injection. Rate of intraocular inflammation is 0.2 or so per injection, in line with prior other studies of intravitreal therapies. Of course, we always pay attention to any occlusive vasculitis events of retinitis, which were none, and no optic neuropathy in between 18 and 24 months. The combined rate of new onset exudation, we have it listed there, 24 months, you have the percentages, nearly 12%, 6.7, and 3.1 in the monthly, every other month in sham group, consistent with prior data. It appears to be a dose-response. The anti-VEGF injections have been tolerated in exudative CNV in our patients. We've had no problems. From what I understand, no concerns from the regulators as well. I think the safety profile has been favorable, and I'm not honestly particularly concerned. It does deserve thorough conversation with the patients about the risk of potential exudative CNV at this rate, depending on the frequency of injections. I always explain what's going to happen with any treatment to my patients, so that is no surprise there. Thank you. It has not deterred patients from receiving the injections at all, and they've done really well with the protocols of the ones that have had the dual injections. It's very helpful. Thank you for the color. I will add to the acceleration treatment, I was very surprised, like you were as well, in a positive way as a scientist. You know, we don't know, but I have a few hypothesis. Cedric explained the one about, you know, dysfunction and aging of the inflammatory system in GA takes years to decades to occur, so it's no surprise that reversing some of this dysfunction may take time. There appears to be this tipping point that's necessary. Apellis has done, I would add, a beautiful job in looking at some change baseline imbalances between the two studies that explain some of the differences in data, and they've been presented at congresses. Some of these may take effect now. The interaction between the drug and lesions changes after 18 months. Because of some of these chance imbalances, it might be a little stronger from 18 months on into DERBY. We don't know why, but we'll keep looking into this, and I'm confident that we'll have more and more data on this. It's fascinating in a positive way. Our next question comes from the line of Yigal Nochomovitz with Citi. Your line is now open. Yeah. Hi, Cedric and team. Thanks for taking the question. Congrats on the data. Just following up on the prior question, Cedric, I noticed your comments regarding the change in the complement biology over time. Just wondering also, could there be any potential drug accumulation effect that might also explain the acceleration in efficacy over time, or is that really not part of the thought process? Yeah. Thank you, Yigal, for that question. Look, anything is possible of course, right? In patients it's of course impossible to measure, but preclinically, we had of course our chronic toxicology studies, and we had no indication in those that there was an accumulation of API in the retina. Unlikely explanation of what we see here. Okay. Got it. Then just with respect to the extension trial for GALE, can you just clarify how that's gonna work with regards to the sham patients? Will there still be a sham arm with which to make comparisons to patients on active drug? Yeah. The answer is no. The way to continue to evaluate these vision size changes is going to be, of course, to look at the slope, right? I mean, the way we've done in these six-month segments, that is a slope analysis. We will continue to do that every six months and to see if the slope changes. In that context, it's very gratifying also to see that the sham control behaved as consistently at almost exactly 1 square millimeter ± 0.05 square millimeters in every six-month segment. A great backdrop against which to evaluate these drug effects over time. Will it be also the every six month looks at the data in GALE, or will it be at a slower frequency? In GALE, every six months we will evaluate the data, yes. In DERBY and OAKS, as you may know, it was every two months. Okay, great. Just one quick question for Dr. Lad. You sort of touched on it already, Dr. Lad, with respect to the prior question. There's some differences between the rates of exudation in monthly versus every other month. Does that in any way impact your thought process around treating with the monthly or every other month or does that not really make a difference for you? For me, it doesn't cause me a great deal of concern. However, I will explain these rates to my patients and we'll make a decision together, at the time of treatment, hopefully after the drug gets approved, whether to pursue monthly or every other month. I will again recommend monthly treatment because in order for them to achieve the maximum benefit and explain to them that they will need to be on drug for longer to see the maximum prevention of deterioration of their retina as well. We'll take all the exudation risk into account and also the every other month data and their comorbidities and age and ability to come in for treatments, just like I do for anti-VEGF these days for my wet AMD patients. It will all go into the conversation, and I think it has to be as part of a careful risk-benefit assessment for every patient. Gotcha. Thank you. Our next question comes from the line of Steven Seedhouse with Raymond James. Your line is now open. Yeah, good morning. Thanks for hosting the call. A couple questions from me. Just first, are there any clinically meaningful visual function differences in those that initiated the VEGF treatment for new onset exudation in the study? Sorry, Steve, you were cutting out a little bit. Can you repeat that? My apologies. Were there any meaningful visual function differences in those that started anti-VEGF treatment for new onset exudation during study? Okay. Yeah, thank you. Typically, Steve, when you have an exudative event, right? It will affect visual acuity. Again, you know, it's worth mentioning the difference between visual acuity in wet AMD compared to visual acuity in geographic atrophy, right? It's the central portion of the vision when you have exudative disease. Most often or very often liquid will affect the central retina and will have an important impact on the visual acuity. Whereas, as Dr. Lad explained earlier, in geographic atrophy, the impact on VA only comes at the very end of the disease when there's already significant vision loss. At that point in time, visual acuity becomes implicated as well. The vision loss, VA loss typically happens when you have the exudative event and typically when you treat with anti-VEGF recovers. Dr. Lad, you are of course the expert. I just want to make sure I represented that well. Yeah. I couldn't agree more. In addition, the N has been small to really gauge a visual function benefit from anti-VEGF, but that's exactly right. These are patients already with GA, with vision loss from retinal degeneration in the dry form. With onset of exudation, the vision would decrease. With treatment, it will hopefully return to baseline or close to baseline. It will not be better than baseline because that is, if you will, the ceiling effect that they have now from dry AMD or GA. The vision will come down and then back up again. The N's been small, and I don't know that. I haven't seen the data yet, so it's hard to know whether it's clinically meaningful. Anti-VEGF of course were approved for a clinically meaningful effect in patients with exudative AMD. Here is a special case because the patients already have a backdrop of GA, so their vision is limited from that. Okay. Yeah, thanks. I think in GALE, you may be even discontinuing VEGF treatment in some patients that developed exudation on study. Any sense of how that's going and if that's proving to be transient at all? Yeah. That's gonna be a fascinating element to study as well, right? At the end of DERBY and OAKS, we stop giving anti-VEGF, and we then do essentially one PRN step to find out how long does it take for these patients to develop exudation again. We don't have data yet. That will be for next year. Okay, thanks, Cedric. A couple more quick ones. Just any comments on microperimetry or reading speed or important previously LLVA or whatever? Yes. Yeah. On all of these endpoints, we basically have, you know, nothing to report there. There are no effects. Now it comes down to doing more specific analyses to kind of establish these relationships between function and lesion growth. That's work for later. It's important to note. Okay, thanks. The FDA got everything that they needed for the review at 18 months, including all the data beyond it. So there's, you know, this is it, the end of the 24-month data and exactly what we needed. For the European regulators, we absolutely expect to have what we need as well. Last question for me is just how important? Based on what the FDA has, is the default of the 24 month data available to them the same as what you're presenting here? In other words, how important is it ultimately for them to have this data you've presented today for a drug label? Because the effect does increase and, you know, there's no new SAEs for ION and the exudation rate's linear. I just, do you think you're sacrificing quality of label by not submitting this, or do they essentially have effectively what we see here? Yeah. That's a very good question. I'm gonna hand that over to Adam, because we have been thinking about that a lot. Go ahead. Hey, Steve, it's Adam. Yeah, thanks for your question. Obviously, in all of the research that we've done with retina physicians, they're very positive on the 18-month data. We expect them to be even more positive based on this, you know, potential compounding effect we see at 24 months. There are various ways that we can communicate the 24-month data, and obviously we'll see a lot more in conferences and congresses moving forward. I think the robustness of the 18-month data gives us great confidence due to the high unmet need that will be perfect for us at the November AAO. There'll be more to come on the 24-month data. Thanks so much for taking the question. Thank you. Thank you. Our next question comes from the line of Justin Kim with Oppenheimer. Your line is now open. Hi, good morning, and thanks for very recent question. Justin, we can not hear anything. I think we lost Justin. Our next question comes from. Wait, wait. Our next question comes from the line of Eliana Merle with UBS. Your line is now open. Hey, guys. Thanks so much for taking the question, and congrats on the update. Just a point of clarification on the EMA and the GALE study. I guess, has the EMA requested any data from GALE in the initial submission? I know it's early on in the GALE study, but just given it's open label, was curious about that. Just a second question, I guess, you know, given kind of the importance, I guess, historically kind of comments around showing trends on functional endpoints for Europe, if you could just update us kind of on your latest conversations with the EMA or the rapporteurs, just on the ability for GA lesion growth alone, even if you don't see these trends, to be supportive of approval and, you know, how you're thinking of around the potential and your confidence around, like, Europe say, you know, saying, "Hey, can we wait a little bit longer and see some more, you know, data from GALE?" I mean, I understand BCVA is not really an appropriate endpoint, but just curious any color or feedback that you've gotten recently from the regulators and your confidence there. I just have a quick follow-up after that. Thank you so much, Eliana. EMA has not requested the GALE data. We got our two rapporteurs, countries. Those are, you know, great countries to work with. They were kind of the top two of our list of countries that we wanted to work with 'cause they understand the retina very well and the functional endpoints. The discussion has been very positive in the sense, as I mentioned earlier, that they want to understand what the long-term impact is of lesion size reductions on the function, right? That does not mean showing something at two years because, of course, we don't yet, right? But to understand what in the long term can be expected. We have what we need to look into that and submit what I think will be a very powerful dossier to the European regulators. Got it. Then just in terms of, like, the foveal versus, like, extra foveal lesion growth reductions, I guess kind of looking, you know, similar after longer treatment. I mean, do you have any hypotheses around why this occurred? I mean, do you think this was maybe just noise on the data or, you know, any particular thinking around the biology as to why we saw this? I think this is incredibly exciting, right? I mean, I would say, you know, it's easy to think now that it was, of course, expected extrafoveal should reduce more in lesion growth versus foveal lesion, but that was unexpected, right? When we saw it last year, extrafoveal lesions grow more. To see more impact initially was something that came as a surprise. I think what is much less surprising is that now after two years of dosing between 18 and 24 that you see essentially those lesions grow responding in a more similar fashion. I'm very excited about this. It is also worth mentioning that we did all possible analyses to make sure that this effect is real, and it is, right? There's absolutely no doubt that this accelerated effect is something that is real, and we can't wait to you know, to continue to study this and to see what it can do for patients. Yeah. Interesting. Thanks. Sorry if I missed this, but just in terms of the GALE study, just given its open label, I guess, how should we think about the timelines for, I guess, when, you know, we could see initial data or learn more about some of the findings? Yeah. As mentioned earlier, Ellie, we have images every six months now instead of every two months. We're gonna wait. We're gonna provide an update probably in the spring sometime when we have a first complete look at six months further. Great. Thanks so much. Our next question comes from a line of Justin Kim with Oppenheimer. Your line is now open. Hi. Good morning. Can you hear me now? Yes. There you are. Oh, great. Great. Great. Sorry about that. Congrats on the data, and thanks for taking the question. Maybe just to touch a little bit more about this, you know, concept of biology. I mean, I'm curious to know, as you think about the better than expected benefits and potential for compounding efficacy long term, do you think that these results could be more unique to C3 targeting MOA? You know, these are sort of things that we had talked about with Felipe and looking at the sort of six to 12 months. Just very curious any thoughts there. Yeah. Thank you so much for that question, Justin. C3 is very different from C5, of course, right? I mean, we've shown that very clearly in the PEGASUS study in paroxysmal nocturnal hemoglobinuria. It's important to note that pegcetacoplan controls both C3 as well as C5, right? The complete complement cascade is controlled with pegcetacoplan. Having said that, we have always hypothesized that the accumulation of C3 product in the retina is what is driving the disease. Therefore, you know, this is a target that we believe in the context of an immune correction is really important. I don't know, Dr. Lad, if you know, you're very familiar with this as well, if you would like to comment on this. In full disclosure, I've recently read the literature on C3 and immunomodulatory effects because of these exciting data. However, broadly, that is exactly right. There are differences between C3 and C5 inhibition, and I think this data will create the impetus to look more into these differences and how it might affect immunomodulation or reversal of immune dysfunction, immune senescence over time longitudinally. It might have, again, important impact for visual function, and the prior question was excellent about the different elements of the complement cascade and how they might relate to effect on function. That's something to take back to our labs, animal models if we can, and patients especially, and use these Apellis data longitudinally from GALE to understand what's happening. We don't know yet, but I think we would really all like to understand. Great. Great. Understood. Maybe for Dr. Lad, one more, if I may. Given a potential for compounding efficacy, can you talk about how you think, you know, the treatment armamentarium and, you know, given that there may be other agents that sort of come and become available as well with pegcetacoplan, potentially, how do you think about comparison of these agents which would sort of follow on that that may not be able to generate the degree of long-term treatment as are being accrued in GALE today? Well, the one great thing about this drug so far that I can see from the cumulative data is, as we mentioned, the benefit. It's beneficial to be on drug for longer duration to achieve the maximum benefit. In addition, the study design was different than other more recent studies in that, it enrolled all GA lesions with no exclusion even of the fellow eye if wet, and that's important because the intent would be to address all GA lesions, help all patients with GA given that no treatments exist. I think this will be a great, broad treatment for all patients with GA in the order that I mentioned that I see right now. As we get more information about other agents, we might be able to refine our treatment and add some more into the mix as we have done with anti-VEGF now since 2005. We've grown more and more confident in our approach to these patients, and we use their individualized imaging, and you know, more of a not precision medicine yet, but hopefully the goal would be to be able to tailor the treatments to the individual patients. This Apellis drug, the pegcetacoplan, is just, it's excellent because it shows this increasing effect over time that's very promising and exciting. I think it would be a good choice for everybody with GA as the first, hopefully first approved future drug for GA. Got it. Great. Thanks for taking the questions, and congrats again. Thank you. Our next question comes from a line of Joseph Stringer with Needham. Your line is now open. Hi, thanks for fitting us in, taking our question. One question for Dr. Lad. Based on patient feedback to date and maybe anecdotally on patient stories, that you've heard in your interaction with GA patients, if you sort of extrapolate that to a real-world setting or outside of the clinical trial setting, how does the conversation go with patients when you explain to them that you aren't seeing improvements in lesion growth, but you're not seeing those improvements at least at two years in the visual acuity and some of the functional endpoints? Does that, when you explain this to patients, how would you think that this would impact their willingness to sort of get that injection, whether it be monthly or every other monthly? Yeah, that's great. You know, this is such an important point to mention. In clinic, all I have to offer my GA patients right now are the vitamins and the vision rehab consult and a lot of counseling about the clinical trial data that's out there. It is hopeful. This, you know, SYFOVRE is the most advanced so far. I do update them after every major congress, and I explain the data and what is revealed. In this case, we know from natural history studies and prior therapeutic studies that failed, which were numerous, that there's a good structure function correlation in scotomas and GA, but not in visual acuity, which, as Cedric mentioned, is a central vision function, and it's nonlinear, it takes a long time to develop, and so it's not a good endpoint for GA. The assessments can be and will be more and more sophisticated of visual function in GA. We've learned a lot more since this protocol was designed, and the regulators actually provided helpful feedback to help academics and industry. We'll get better at structure function correlation and showing to the patients where the functional benefit is in their individual lesion. I do explain to patients we know that GA vision enlargement means loss of function with an enlarging blind spot in that location. They get it, and they actually can see it. They can draw it for me on the Amsler grid oftentimes. They show me where their absolute scotoma is and where, which is the total blind spot and then a relative area that retina is really thick and dysfunctional. They get it. They want to prevent further progression. If they lost one eye already to GA centrally, they're very careful about their second eye. They love for me to show the imaging on autofluorescence, which is the primary endpoint of the study, to show them that the lesion is not yet in the fovea, and we're trying to prevent that from occurring. That's how my conversation goes with patients. They instinctively understand what we're seeing. I think we have enough data to back up what we're seeing, and we'll have more and more data in the US submission and from GALE. I think the study will be a goal line. I would also add microperimetry has improved since the prior studies. The technology is much more robust, user-friendly, and the data are reliable and reproducible. We've had issues with that assessment before, which is not the case now. We've gotten better. Also, our software tool structure function, we can do overlays of structural function, which are time-consuming. That's why we don't have the data to talk to you about now. This is fresh off the press. There's a lot that can be done with this, and I think we'll have the tools to show the patients how this will impact function, preventing functional loss over time. Great. That's very helpful. Thank you so much for taking our question. Our next question comes from the line of Douglas Tsao with H.C. Wainwright. Your line is now open. Hi. Good morning. Thanks for taking the questions. Just maybe, to sort of simplify, I think part of the question, I think that some people have asked to Dr. Lad. Just when you think about your patients, I mean, it sounds like you have personally sort of, as a clinician, have a bias towards the monthly dosing. But just when you think about your patient population and the and the considerations, that patients could have in terms of what treatment they might opt for, in the end, what do you anticipate would be the sort of proportions who would go on to monthly therapy versus the every other month therapy? Then also, I'm just curious, you know, do you have a sort of set of patients who are anticipating approval and are looking to get on therapy as soon as possible? Thank you. Oh, thanks. Great questions. The patients generally with GA are very engaged, at least the ones that come to our clinics, because they see counseling about their disease progression and what therapies are in the pipeline. Of course, this is the most advanced promising program right now. I think to answer a question about the two months versus one month, I think this will come down to individual patients' characteristics. In this particular study, as I understand, about 35% have been extrafoveal and 65% foveal, and that was the makeup of the patients in this study. If the patient's already lost one eye, they're very motivated. My suspicion would be they really want the monthly treatment to be able to prevent further degeneration. In addition to vision concerns, a lot of other factors come into play, which is their age, transportation, and comorbidities. It's hard to predict. My guess will be it'll be about half and half. In the end, half will be very motivated and want to be extremely proactive and choose the monthly. Others will say, "You know, every other month will still give me 80%-90% of the benefits from clinical trial data, and this is almost as good, and this is sort of all I could do right now with my age and other health issues." We do this for anti-VEGF. We tried. That's why we do treat and extend with anti-VEGF. This condition might be a bit different, and we'll have to take their individual characteristics into account more. With anti-VEGF, we do careful treat and extend to be able to tailor a regimen to minimize the burden while maximizing the benefit. That's what we like to do with this down the road. Okay, great. Do you have patients just waiting to go on therapy who are aware of this treatment being potentially close to approval? They cannot wait. I can tell you they cannot wait. That's why they appreciate the updates from various meetings, 12, 18. They love the 24 months data I'll share it in clinic today because they would like to see this closer to approval, and they'll be very motivated to start. Great. Thank you. I'm showing no further questions in queue. I'd like to turn the call back to Dr. Cedric Francois for closing remarks. Thank you, operator, and thank you everyone for joining our call today. Today marks another important milestone for us here at Apellis as we continue to establish ourselves as a leader in complement and work to bring pegcetacoplan, a first-in-class treatment, to the millions of patients living with GA. We look forward to updating you on our continued progress, and have a wonderful day. Thank you.