Apellis Pharmaceuticals, Inc. (APLS) Earnings Call Transcript & Summary

All right. Hello? Hello? Okay. How does it feel to be at a live event? Feels good to me. All right. Well, welcome, everyone, to Apellis' R&D Day. It's an incredible joy to have you all with us here in person and the people following on the web. Before we get started, I think it is worth kind of taking a step back to the year 2017 in November when we went public. That makes us, I guess, 4 years old as a public company, which makes us like senior citizens in the IPO world of today. And -- but looking at that moment in 2017 after -- just after we had gone public, and we sat down and determined that it would be our singular mission to become the world's heavyweight champions of complement. And that wasn't because we were being arrogant, because we understand how complement is complicated, but we did that because we have such a desire to explore what complement can do in a broad range of indications across all of these therapeutic areas. Because this ancient part of our immune system is just so involved in so many diseases. But at the time, we also realized that, that was a pretty grand ambition for a small company coming out of Louisville, Kentucky. So we decided to put most of the attention in the years after that on our late-stage developmental programs. And we now have Empaveli on the market for PNH, and we are about to read out our Phase III clinical trials in geographic atrophy. But back then, we sat down with our Chief Scientific Officer, Pascal Deschatelets; and our Chief Innovations Officer, Lukas Scheibler, and we decided to set them free. And we said, your mission is quite simple, own complement, own it today, own it tomorrow, own it 20 years from now. And what you're going to see today is the culmination of that effort over the past 4 years and how it integrates with all of the other work that we've been doing and that you're much more familiar with. So hopefully, you will enjoy it as much as I have, and we all have adapted this. And again, welcome to 3 hours that we've been looking forward to for a long time. So these are our forward-looking statements. We also have a couple of amazing KOLs with us across the therapeutic areas that we are going to cover. So thank you, Bruno, Angela, Nancy, Matthew, Ileen and Charlie for joining us. And a small shout-out to our partner in Europe, Sobi, who is helping us to commercialize our systemic product outside of the United States. So this is what Apellis looks like today with a focus on rare disease, of course, with Empaveli kind of leading the charge there in PNH, in ophthalmology, where we have an ambition to be #1 in the retina. And we say that mostly because geographic atrophy plays such an important and central role in the retinal practice and where we are hoping to make a big difference. And then this new therapeutic area, neurology, where we've done a ton of work and where we are now ready to start thinking about clinical trials as well and which we will hear much more. So what you have to look forward today is, in the rare diseases, we'll talk about the launch, kind of the first Empaveli and other rare diseases, the 4 new registrational programs that are ongoing or about to start. And then we'll talk about the new molecular entities that are in development to sustain the long-term growth, both in the existing and the new indications. In neurology, we're going to talk about the role that C3 plays in a wide range of neurodegenerative conditions and how we plan to pioneer targeted C3 therapies in these conditions. And in ophthalmology, we are optimistic heading into the DERBY and OAKS readouts in September of this year, just a couple of months away. Again, it's hard to overemphasize how important this disease is and how terrible this disease is for the patients affected by it. And hopefully, we will be able to provide what would be the first solution or the first therapeutic opportunity for patients with geographic atrophy. And in ophthalmology as well, we will then talk about the new molecular entities that we have been working on. And with that, I'm going to hand the word over to Vicky Brown, who heads our rare disease program, to take us through what we have been doing there. Vicky?

Okay. Good afternoon, everybody. I am delighted to be with you here today. As Cedric mentioned, I get my formal name on the slide today. So Victoria or Vicky Brown, and I head up and lead our rare disease programs here at Apellis. So what we are going to go through, but I will start with really how we think about our approach to rare disease at Apellis, but also Empaveli in particular. And I think when they say you have a pipeline and a product, Empaveli really personifies what that means. And it's through the comprehensive control of complement that only Empaveli can offer is why we believe we will be able to transform the way that complement-driven diseases are managed. So you can see here our vision to achieving that, and we'll talk through the plans over the next 90 minutes of how we believe that ambition will become a reality. We have 3 parts to that strategy. We will start off with how we were going to build that foundation of Empaveli in PNH. And then we will talk about how we'll expand into future indications and disease areas, which all require that comprehensive control of complement with Empaveli. Then we'll also talk about how we plan to enhance the patient experience through improved dosing administration as well as dosing frequency. We'll also talk about, as Cedric mentioned earlier, how we will then expand our portfolio beyond Empaveli with new assets to improve, but also to further expand our list of future indications. So I think as you guys well know, we always have a lot going on at Apellis. So with that, we're going to crank through the next few sections. And I'm delighted to welcome David Acheson to join me, who is going to take us through some very early indicators of the impact that Empaveli is having on the PNH market in the U.S.

Thank you, Vicky. Appreciate it. For those of you who I've not met, my name is David Acheson. I'm responsible for the commercial business in North America. And my team and I are -- it's the first time I've had a chance to be with all of you and very excited to share today where we are with the PNH launch up to this point in time with Empaveli. It's been an exciting 6 weeks since PDUFA approval and the launch. And I'm going to try to give you a quick overview of kind of where we've had some successes and what this looks like. So first of all, one of the things that was mentioned earlier by Cedric is that we're off to a strong start with the launch, which is true. And I'm very excited to also tell you that the imperatives that we put out and the priorities that we put out to really make sure that we had an opportunity to have good commercial supply, to make sure that we had ourselves set up commercially so that we could start to really introduce Apellis in the market to us as well as adapt the marketplace to the unmet need that's out there and make sure that, that was well known and established. And ensure patient access and reimbursement, which I'm going to talk a lot about in just a few minutes. And then really leverage that clinical data, everything is underpinned with the clinical data, and we're so excited to be able to do that with the label that we've got. And that's one of the reasons why I think we're off to a really good start to begin with in the last few weeks. I want to start with some early indicators. On the left-hand side of the slide, you're going to notice that information you've probably seen before. There's about 1,500 patients that are in the marketplace that are currently treated with a C5. And there's about 150 patients that come in that are newly diagnosed every year that are now diagnosed as PNH patients. Our label allows us to have access to all of them, and that's been very exciting for us because we have an open label. And that's helped both at the payer side of discussions as well as with our physicians. I will tell you that in the treatment that we're starting to see come through today, about 60% of the patients that are switched from a C5 are coming over from Ultomiris, which is very good to see. And it also tells you that the unmet need still exists even with the product that's in place today. And we've also got patients that have come in that are naive that were newly diagnosed and have been put directly on Empaveli to start, which is good news early in the launch. I'm not going to go through the quotes on the right-hand side of the slide. I will tell you a quick story, though. So one of the things that we happen to have is a good -- really good medical affairs team. You're going to hear from Monica later. And we have a number of people that are interacting with patients. And one of the things that has come up in the discussions is stories about patients' lives and what's going to change by going on Empaveli. There's a patient that talked to one of our care coordinators that said, "Hey, listen, this is an exciting time for me because I don't have to go into the oncology clinic and watch oncology patients only get to ring the bell when they're done with their treatment. I get to ring the bell too. And I have a chance to go home and be with my kids and be treated at home and have more flexibility." And she actually switched over from a C5 and is now on product at home as of 2 weeks ago. So it's a life changer for folks like that, that want to make a shift in the way that their daily lives are impacted. On the left-hand side of this slide, this is around the market access work that I talked about a few minutes ago. We've had a lot of impact here. Because the label is written the way that it is and the data is the way that is in there with a head-to-head with Soliris, we've had a lot of interest from the payers. Our -- obviously, our priorities are to leverage the clinical data, make sure that we have access for patients across the board, even if they can't pay for it. And we have multiple programs in place to be able to get patients transitioned over from a C5 or to start with Empaveli at any point in time. And the last one is, we do believe strongly that we're going to remove costs from the system based off of at-home treatments and transfusions that will come down for patients that are currently transfusion-dependent. We have 20 plans that our market access team are calling on today. They've had a clinical presentation with all of them, which is 100% across the board. That covers about 80% -- 85% of all PNH patient lives today. So the interest has been high. 4 of those major plans have put us on an accelerated formulary review process for late Q2, early Q3. I would have expected a couple of those plans because I know them to be way back in the end of the year. And one of those plans has already put us in a positive formulary position that allows patients to have access PA to label, which is fantastic for us. And there's a lot of momentum in here. I'm very excited about what we're seeing with the payer engagement and with the access for patients through market access today. On the patient journey, this has been something that's really near and dear to our heart and culturally something that Cedric has put into play is how important it is for the patient to have a good experience and where they can have access to the product. So we have Apellis Assist that is set up for those patients to have direct access to care coordinators. We actually have nurses that go into the homes of the patients to train them when they transition from a C5 or if they start on Empaveli. And they get trained in their homes, in their setting by somebody that can come in and see them. On the managed care side of it, we're actually seeing patients from all segments. So about 50% of the patients today are in a government segment, either Medicaid or Medicare. And the other 50% are commercial. We've seen patients come through the process, be approved through a PA and are now on product from all 3 channels, which is really good news early in the process. And we've only actually had one true denial. So that opportunity for us has really gone through a lot -- number of patients have gone through without any issues, and we've only had really one denial that we've had to deal with to work with the plan, and that's very early in the process. On average, patients are getting on products between 7 and 10 days, which is also good news. It's right on target and exactly what we were planning for. And we have more than 50 physicians that have enrolled in REMS, which is an early indicator of not just demand, but patients that have a need and physicians that have identified that the product can help them. So finally, I just want to wrap up with a few quick comments. On the left-hand side of the slide today, we've done a lot of work to get ready to prep the marketplace, the field teams, the medical affairs teams. Our entire organization is focused on the launch right now. We're about 6 weeks in, and it's still very early for us to manage through a number of things that we can see coming as far as opportunity. I've been very pleased operationally. We've had a very good launch overall, and I'm super excited about what's yet to come. By the end of the year, I expect that we'll be at 90% of our plans will have us in a position on formulary that's PA to label. We've engaged or will have engaged with 100% of our top accounts and around 85% to 90% of our total top physicians across the country. And the one thing that we have done, and you'll see on the bottom of that slide, is we have already done surveys with our patients that have been onboarded to the product. And we've had very high ratings on 2 things. One is the tools that they're receiving, and you'll see some of those materials that are out in the lobby. And two is the way that they've been trained and onboarding for them to be able to start the product, which is very good news. And we expect to maintain that and continue to grow that over time. I look forward to having a chance to answer some questions in a little bit when we do a panel. Right now, though, I appreciate the time this afternoon. I'm going to actually introduce Monica Fay, who is our Senior VP of Medical Affairs; and Dr. Ileen Weitz to please come up to the stage, and I'll hand it over to them.

Thanks, David.

You're welcome.

Thanks. So thank you so much for the opportunity to be here. And I'm very pleased to be joined by Dr. Ilene Weitz. Dr. Weitz is a Professor of Clinical Medicine at the Keck School of Medicine with the University of Southern California. And she was kind enough to fly from California. So it's a quick trip, and we are very appreciative of you making the journey. So Dr. Weitz White's completed her medical degree at the Medical College of Pennsylvania. And after that, she completed a residency in internal medicine at Cedars-Sinai Medical Center. She went on to do a fellowship in hematology and oncology at Scripps Research Clinic in La Jolla. And since then, she's been practicing at USC. So we're happy to have her here with us today.

So Dr. Weitz, I know that you've been involved with the development of pegcetacoplan for a number of years. And that's -- now it's Empaveli. And so we'd love for you to be able to share your experiences as being an investigator in the program and what it's meant for patients. So with that being said, could you help us understand a little bit about your practice and what your practice in PNH looks like?

So I am a nonmalignant hematologist. I don't do much in the cancer realm, but primarily concentrate on nonmalignant disease or what we like to call diagnostic hematology. And I was trained by the dinosaurs. So I had a lot of experience with PNH. And actually, before I went back to the university, my reputation in private practice was based on diagnosing a case of PNH. And we had a lot of cases. We have a fair number of cases at the county hospital. And I have a fair number of cases on the private side. I follow about 35 to 36 PNH patients. So it's probably the most PNH patients in the west.

Absolutely. And we mentioned that you earned your reputation on diagnosing of PNH patients. So to see the field come so far, I'm sure it has to be rewarding to see that progression in the development of treatments and also the way that we're managing PNH. So to that end, I know that the results from PEGASUS were published just a few months ago, and you were an investigator in that trial as well. Could you share your thoughts about the overall results and how you interpret and how you think about the results of PEGASUS?

So we had actually had patients on the PHAROAH trial before PEGASUS. And 2 of those patients rolled over into PEGASUS, and the results were really quite outstanding. All of the patients became transfusion-independent, those that continued in the trial became transfusion-independent. One of the patients I was able to do phlebotomy to remove her iron load. So I took out probably 10 liters of blood, which is extraordinary. And she was able to maintain her hemoglobin in the range of 11 to 12.

So with that in mind, what did it mean for patients to be a part of the development of pegcetacoplan? They had been managed with C5 inhibitors. And then with a new mechanism of action, they had a chance to enroll in a trial. What was that experience like for them? And how did they relay that to you?

Well, it depended on what arm they were on. As you know, the PEGASUS trial was randomized. I did have 1 patient who was randomized to the ecu arm and was not happy about that. But the patients were willing to try this because they were -- they were all still significantly anemic. And the promise of having a more normal hemoglobin and potentially having -- not having to come in every 2 weeks because this is before -- we started this before ravu was approved, was pretty appealing to them. And they could travel. One of my patients has taken her little pump with her whenever she travels. She was able to even go to Europe. So before that, they were pretty much tied to staying home and getting their drug every 2 weeks. And then if they switch to ravu, then they would be -- they have a little more leeway in terms of space to do things.

So in addition to having that space to do things, being able to travel, what did your patients communicate as far as how it made them feel? What was that impact beyond the more normal hemoglobin and beyond the ability to have a bit more freedom?

Well, the patients -- it depends on where the patient is coming from. So a lot of the patients, especially those that were transfusion-dependent never felt good. And we already knew from the C5 inhibitor trials that transfusion didn't make them feel any better, because that's not what's driving their symptomatology. It's the complement that's driving the symptomatology, the fatigue, et cetera. So to -- so they never felt better when they were transfused. So it's not that hemoglobin per se, but the inhibition of the complement that's really making them feel better. And on treatment, they felt much better.

Yes. So it sounds as if, overall, that more comprehensive control was leading to them feeling better.

Yes. So I would say about 30% of my patients have a pretty normal hemoglobin. But that means 70% of them don't. And of those, probably another 1/3 or still -- they weren't pretty low. I mean we don't transfuse like we used to transfuse. But they run pretty low hemoglobins in the range of 8% to 7.5%. And the vast majority sit right in the middle, so they run between 8% and 11%.

Okay. Great. So one of the things that we also think about with Empaveli, it's a new mechanism. It's new to the market as of just about 6 weeks ago. And we know that we still need to continue to understand what the long-term efficacy and the long-term safety is. And I know from a safety standpoint, you and I were talking about this earlier, first, do no harm. And so part of that is looking at that long-term safety profile. Some of the things that often come up in the context of PNH patients are breakthrough hemolysis and what does that look like for patients. And I know that in the PEGASUS trial, there wasn't a lot of flexibility, just given the fact that it's a clinical trial. But I'd love for you to tell us a little bit more about how you think about breakthrough hemolysis and management and what are some of the priorities that you have when carrying for your patients.

So breakthrough hemolysis is a real problem regardless of what drug you're on. Because if you have excess complement activation, it doesn't matter how much blockade you have. If they're experiencing symptoms, then everything is lost. So you can always -- hemolysis is the least of the issues, it's the symptom. But the bigger concern is the risk of thrombosis in these patients when they break through. I've had a couple of breakthroughs. The clinical trial was extremely limited in how much extra pegcetacoplan we could use. So that made it very difficult. But more recently, with the change in the strategy, I was able to rescue one of my patients who had a viral syndrome and broke through.

Yes. And I think that will be important as we get to the real-world setting. Physicians have that flexibility to best manage their patients. Another thing that comes up with safety in PNH, and we know with complement inhibitors that there can be a risk of infections. And we know that there is a risk of meningitis in patients who have complement inhibition. So far, we're at about 350 patient years of experience with Empaveli. So we've got a long ways to go. To date, we haven't seen any cases of meningitis. Any thoughts on that and how you best prevent those infections in your patients and the importance of vaccination?

Well, everybody is vaccinated for everything. So they're vaccinated for meningococcus with the quadrivalent. They get MenB, and then they get vaccinations for all the other encapsulated organisms. So everybody is vaccinated. But interestingly enough, one of my patients is a nonresponder to vaccines. She had 0 response to the meningitis vaccines. And she's been vaccinated 4 times and finally refused another vaccination.

Fifth time wasn't going to be the charm.

And she has not had any infections. She is supposed to be on penicillin prophylaxis. I cannot swear that she takes it. But that's -- my other strategy is to put them on penicillin prophylaxis. And everybody, all my C5 patients, C5 inhibitor patients and the C3 patients are on penicillin prophylaxis.

Great. So one of the more recent pieces of information that we had shared with Empaveli as the results from the Phase III PRINCE study in treatment-naive patients. And so we did see an increase in hemoglobin relative to the standard of care. As well as those patients who are treated with Empaveli, the majority of them became transfusion-free relative to standard of care. So while we haven't been able to share the full results yet, we hope to do that later this year. I'd love any preliminary thoughts on what you think that means, especially given your patient population.

Yes. Well, we didn't participate in that trial. It was done outside the U.S. So -- but it presents another option for patients that they could go directly on a C3 inhibitor and not even have to go on to ecu or ravu. So it does present another opportunity for patients to use a different strategy. And we know that a significant number of patients who are on the C5 inhibitor do have extravascular clearance that is significant. I mean even my patients who have normal hemoglobins have high retic counts. So they all get extravascular clearance. It's just a matter of how symptomatic they are from that.

So when you see those patients who have the high retic counts and who you think who are having that extravascular hemolysis, given that we now have additional treatments, there's more that are underdeveloped -- under development, how do you start to think about that treatment landscape of the future, which is pretty different than it was 15, 20 years ago?

Well, that is an interesting question. So there are things we know about C5 inhibition that are important and that those drugs are not going away. So the strategy is going to be, can I pick a patient who might be better for C3 inhibition versus not. My strategy would be if they have a high retic count, I would certainly consider it, going on to a C3 inhibitor. If they have a low retic, i.e., they have some component of aplasia or hypoplasia, that patient is not going to do as well. And that's what we saw in some of our patients who are on the study. When their retics dropped out, they just didn't do well.

Yes. So thank you for sharing. And last question, and we'll open it up for the audience. But for you as a clinician, for you as a researcher who has been in this field for a while, what does it mean to you to have a new treatment approved for your patients with PNH?

Well, first of all, complement was a system that was totally forgotten by everybody. So Wendell Rosse used to say -- said to me that we made a good team because he knew complement and I learned -- I knew hemostasis thrombosis. So everybody knows some hemostasis thrombosis, but no one knows complement. And it's a fascinating system and it's integral to so many diseases that we see. And so I think that it's fantastic to see the evolution of these medicines, both in terms of lower complement, terminal complement inhibition, then C3 inhibition, then higher complement inhibition. It's really quite fascinating. And I think we're going to see a lot of new drugs coming out and new indications for these.

Yes, absolutely. And we'll learn about some of those where complement plays a role today. So with that, I'd love to open it up to the audience for any questions you have for Dr. Weitz before she heads back to California. Raise your hand, yes.

This is Madhu Kumar from Goldman Sachs. On the question about other kind of drugs in the complement space, a question we kind of think about a lot is, obviously, there's a new, renewed focus on the alternative pathway and drugs that target the alternative pathway as kind of additional approaches to going after PNH. So on a very practical basis, what would motivate you to switch a patient off a drug like Empaveli to a drug like an alternative pathway inhibitor? And like what would those drugs deem to show you to really convince you to take someone who is well managed on a drug like Empaveli and put them on to an alternative pathway drug?

Well, I think what you're going to see is that, number one, it's probably going to be patient-driven, because B and D inhibitors are oral. And I think that's going to have a big impact. But it would depend on the patient, I guess, and what works best for them. Not everybody is going to want to do a subcu injection 2 or 3 times a week. Other people may not feel that an oral drug is going to be appropriate for them, that it may not work as well. We don't know that. And the data we have on D is overlapped. It's all overlapped with a C5 inhibitor. So we're going to have to see the data of patients who come off the C5 inhibitor and are just on D or B. So I think that may have a role.

Yes?

Matthew Luchini from BMO. Just was hoping you could talk a little bit -- you obviously have patients from the study that are on Empaveli now. If you could tell us a little bit about how your nontrial patients are planning to be switched, if at all and what -- how much of that will be patient request-driven versus you sort of poking and prodding? Just any additional color on how you think your treatment breakdown may compare today versus, let's say, end of the year or a year from now?

Well, they're all ready to switch. I mean they're not going anywhere, because we don't -- they remember what it was like when they were on a C5 inhibitor, and they were highly transfusion-dependent. So -- it's just a matter of my writing the script for them to go on to commercial drug. But they're not coming off. And B and D, we do have 1 D trial open. Again, an overlap, and they're not eligible for that because they're not on ecu or ravu. So they're going to stay on. They're happy about it. Yes. I mean they're in a really different place than they were at the beginning of the trial.

Yes?

Phil Nadeau from Cowen. Just to follow up on that last question. You mentioned 3 patient groups in your practice broadly, 30% with normal hemoglobin, 40% with values between 8 and 11 and 30% between 7.5 and 8. Can you talk about the switching strategy for each of those groups independently? Are some of the patients like the very low patients going to go on combo therapy for a while and then you wean them off Ultomiris? Or conversely, the normal hemoglobin, will you just rapidly switch them? Like how are you going to -- in those 3 different groups, how would you integrate Empaveli into your treatment?

Yes. I probably would leave my normal hemoglobin guys alone because they're doing really very well at the moment and rethink what to do with them. In terms of the patients who have hemoglobin between 11.5 and 8.5 or 9, some of those patients, it would be worth switching them. But they're going to have to overlap. There's always going to be an overlap. And all -- pretty much all of my PNH patients are on ravu as opposed to ecu. I only have 1 or 2 who have not switched. Most -- I think all my PNH patients with one exception has been switched. I have a few patients who didn't do as well on ravu as they did on ecu and have switched back to ecu. Those patients, some of them may be ideal candidates. In fact, there's one that's been switched now. Yes. But there's always going to be an overlap. And it's -- I believe it's written in the package insert how exactly to do it. So you want them when they're at kind of the height of their inhibition to start on the new drug because it's going to take a couple of weeks to get to therapeutic levels.

Yes. I'm guessing probably similar to that was on the clinical trial, at least a 4-week overlap is what I'm thinking.

Yes, that is pretty much what the strategy is.

Other questions?

It's Tazeen Ahmad from Bank of America. Dr. Weitz, just wanted to ask you a question about your treatment-naive patients. So what is the profile of a treatment-naive patient? So is it somebody who has just been diagnosed? Or is it a patient who might have been diagnosed that for whatever reason has not been put on therapy yet? And can you give us a sense of what kind of split, ultimately, you'd have between switched patients as well as treatment-naive patients?

That's a really good question. So I have 2 or 3 patients who have been diagnosed with a PNH clone, but who are asymptomatic, and their LDH is doing quite -- meet criteria. And they're otherwise doing very well. Their D-dimers are low. So I'm just following those patients. But once clone has steadily increasing, so she's probably going to be eligible for treatment soon. So it's going to be a matter of having a discussion with the patient as to whether or not they are willing to do subcu at home or whether they want to go on something like ravu.

What would you say is the greatest rate limiting factor for you to prescribe right now?

The greatest rate limiting factor, getting it in sort of -- well, I don't even have to get it into my formulary anymore because it can be done at home and home care can take care of it. So that's off the table, which is great. And I don't have to deal with the hospital pharmacy. So that would probably be helpful. But the biggest barrier is going to be insurance authorization. That is always the biggest barrier.

Ellie Merle from UBS. Just a question on the clinical data and the endpoints that you think are most important, particularly when we compare it to some of the emerging data sets from some of the orals. I guess what are the endpoints that you're looking at when you compare? Are you looking at hemoglobin, LDH levels? Is there a certain LDH level that's sort of sufficient? Or is it the lower the better? Just curious how you're thinking about some of these endpoints as some of these data sets emerge.

Well, number one, in PRINCE, the LDH was not -- did not go down to normal, but the dosing was different than in the current -- in the PEGASUS trial. In PEGASUS, they were all on a C5 inhibitor, so they all started at a low LDH. So you can't really use LDH if you're switching the patient. Obviously, if the LDH pops up, that's not a good thing because that's worrisome. But you really need to look at the bilirubin and the retic count and the hemoglobin. And they should be kind of inverse. If the hemoglobin goes up, the bilirubin goes down and the retic goes down.

Alethia from Cantor. Just a couple of questions, one, on the treatment-naive population. Just how do you think about incorporating possibly this regimen into that? And like what are the factors? And then I'm just curious, like from your perspective, do you feel like kind of the incidence of PNH is consistent?

Yes, I don't think that the numbers have changed all that much. We're better at diagnosing it. I mean the days of the Ham test -- I grew up in the days of the Ham test, not going to happen. It's gone. So it's pretty easy to send a flow cytometry and to get a diagnosis. You just have to think about it on your differential diagnosis. And that's where the problem is with diagnosis for PNH. And so the patients kick around for several years before they get a firm diagnosis. So -- but once they are diagnosed, then now we have this option. So it's just a matter of getting it through the insurance company and getting the patient to decide which route they'd rather take.

And then just talking about the PRINCE data set, like the naive, like where would -- where do you see that fitting?

Well, I think that would be ideal to get the patients straight on PEG. And the data was actually pretty good. You get a pretty significant improvement in the hemoglobin. The thing that has -- they need to analyze is the D-dimer data and how it affects hemostasis, but has the same suppressive effect as a C5 inhibitor.

And we anticipate full results from the PRINCE data being presented later this year. So -- all right. We have time for one last question.

Justin Kim from Oppenheimer. You mentioned that the majority of patients are on ravu. And could you just talk a little bit about how the switches have gone from ravu to C3? And to what extent you leverage any of the flexibility, I think, that switch allows for relative to ecu?

Well, on the trials, on the PEGASUS trial, it was only ecu. They didn't allow ravu, which presents its own challenges. I mean ravu has a really long half-life. So the half-life is 50 days, 51 days. So you're talking like 6 months before the levels are low enough to be able to see that the C3 is adequate or inadequate. We have more flexibility in the commercial -- commercialization of the drug that we can adjust the dose more than we can with -- than we could on the clinical trial. So I think that will change. But it's going to be true for all the new drugs, the vast -- outside of the U.S., the ravu is relatively rare. But in the U.S., the vast majority of patients are on ravu.

Great. So thank you so much for joining, and thank you all for your questions. So we'll be back for the broad Q&A. Dr. Weitz will be leaving us to head back to California, but thank you so much. And with that, I will turn it back over to Vicky.

Really nice to hear how things play out from clinical development and then into the real world and the impact that Empaveli is clearly having in the U.S. on PNH. We'll pivot now on to the second part of our strategy and talk about how we're expanding and growing our list of indications, building off that foundation that we've set in PNH. And you'll hear from a variety of key opinion leaders within each of our areas of focus, on nephrology, neurology and hematology, but all focused in disease areas where we believe that, that comprehensive control of complement through Empaveli is best positioned to provide the best possible outcome for patients living with these devastating diseases. So with that, I'm going to hand this over virtually to Dr. Pickering. He is based from Imperial College in London, who is going to talk us through our nephrology indications.

Thank you very much. So my name is Professor Matthew Pickering. I'm Professor of Rheumatology and Wellcome Trust Senior Fellow in Clinical Science at Imperial College London. I have a long-standing research and clinical expertise in complement-mediated kidney disease. And I'll talk to you today about immune complex membranoproliferative glomerulonephritis, which I'd refer to as IC-MPGN and C3 glomerulopathy, which I'll refer to as C3G. So if we can have the next slide, please. These are rare chronic kidney diseases, which result in progressive kidney damage and renal failure and with a similar clinical presentation and cause. They're both characterized on the renal biopsy by abnormal accumulation of complement within the glomeruli, the filtering units of the kidneys. But they can be distinguished by the presence of immunoglobulin. In C3G, there is little or no immunoglobulin, resulting in C3 dominant deposits. In IC-MPGN, there is immunoglobulin and which can be equivalent or indeed even more than that of C3. And these findings implicate abnormal alternative pathway activation in C3G and abnormal classical and alternative pathway activation in IC-MPGN. A further differentiation derives from the morphological pattern of the glomerular injury. In IC-MPGN, as its name indicates, there's membranoproliferative glomerulonephritis. In C3G, there may be widespread electron-dense change in the glomerular basement membrane, which is characteristic of the dense disease subtype or predominantly subendothelials deposits, which is typical of a subtype we call C3 glomerulonephritis. And there is considerable overlap between these conditions. Next slide, please. There are no effective or approved treatments, and the key clinical signs are nonspecific. And the renal biopsy is required to be confident of the diagnosis. Clear to the presence of C3G is the finding of a low level of circulating C3 in the presence of normal C4 levels, indicating abnormal alternative pathway activation. The images on the left panel shows the typical glomerular complement staining profiles in C3G, where you see C3 staining with little or no immunoglobulin. On your right, the typical findings of IC-MPGN where there's immunoglobulin staining in addition to C3. Next slide, please. These conditions represent areas of high unmet need. Approximately 50% of individuals will reach end-stage renal disease between 5 to 10 years post diagnosis. An importantly, the conditions recur in the transplanted kidney. Proteinuria and the estimated glomerular filtration rate, eGFR measurements in the clinic are used to monitor the renal disease. Next slide, please. And perhaps not surprisingly, the condition impacts detrimentally on quality of life. These quotes from Chase, who has C3 glomerulopathy, are really typical of what I hear in my clinic and during patient family meetings. Next slide, please. So based on what we understand from detailed research into the causes of the abnormal regulation of complement activation in C3G and IC-MPGN, we need to stop the abnormal activation of C3 in this condition. All the complement pathways trigger activation of C3, which in turn triggers activation of C5. And the consequence of this is the production of biological mediators that cause kidney inflammation, C3a and C5a; and also structural damage to the kidney, C3b, C5b. And the membrane attacks complex illustrated as MAC here. Next slide, please. And importantly, EMPAVELI, through targeting C3, prevents the production of these detrimental mediators of both the level of C3 and C5. Next slide, please. So DISCOVERY is a Phase II proof-of-concept trial designed to assess the safety, tolerability and efficacy of pegcetacoplan in several renal diseases, including C3 glomerulopathy. The primary end point in the study was change in proteinuria from baseline to week 48 as determined by 24-hour urine collection and protein creatinine ratio. And additional end points included change in serum albumin from baseline, change in the eGFR from baseline and, of course, assessments of the complement systems such as the C3 level, plasma soluble C5b-9 and functional testing of complements with the CH and AH50. The enrolled patients needed to be at least 16 years of age with a C3G diagnosed by historical kidney biopsy not for clinical reasons. And they had to have significant proteinuria, urine protein creatinine ratio, of at least 0.75 mg per mg and an eGFR of equal to or greater than 30 mls per minute. Eight C3G patients were enrolled in this study, and I summarize the results today. Next slide, please. So 5 patients were included in the efficacy analysis. The remaining 3 were excluded due to disruption in study drug dosing, and the primary end point was changed from baseline in proteinuria at week 48 based on 24-hour urine collections. The mean at baseline was 3.4 mg per mg, which declined to 0.93 mg per mg by 48 weeks of treatment, so a 73% reduction in mean proteinuria. And along with this, the average serum albumin rose from a low normal range into the normal range, as you can see on the table on the right. And renal function, importantly, as measured by eGFR, remained stable throughout this 48-week period. And collectively, these data demonstrate that pegcetacoplan has the potential to improve measures of renal damage and maintain renal function in patients with C3G. Next slide, please. Consistent with its mechanism of action, blood-based markers of the complement system improved. Serum C3, shown on the graph on the left, increased from the low range to above the normal range, reflecting an increase in the pool of bound C3 to the study drug. An increase in C3 is clearly important because activation of C3 and deposition of the C3 breakdown products, as I mentioned earlier, are thought to be the key drivers of kidney damage in this disease. Soluble C5b-9 levels markedly improved over the study period, reflecting the targeted correction of uncontrolled complement C5 activity. The CH and AH50 were not significantly changed over the study period. And this is consistent with C3 inhibition that is not complete, i.e., leaves some residual complement activity, which may be important in protection against infection. And the C3 inhibition was estimated to be around 80% to 90%. Next slide, please. There were no severe or serious adverse events and no discontinuations due to adverse events in the C3G patients. And the majority of treatment-emergent adverse effects, TEAEs, were considered unrelated to study drug. Next slide, please. So collectively, the C3G data from DISCOVERY are encouraging, I believe, and demonstrate that pegcetacoplan should be further investigated in this group of patients and in complement-mediated glomerular diseases more broadly. And that is why Apellis is pursuing pegcetacoplan in a Phase II and Phase III study in patients with IC-MPGN and C3G. In the Phase II study, the goal is to get a rapid understanding of how the drug impacts kidney pathology in posttransplant patients. The goals of the Phase III study are to demonstrate pegcetacoplan's superiority over standard of care. The primary end point will be based on proteinuria and the estimated glomerular filtration rates, which, as I've said, are key clinical measures of disease activity. And of course, other disease parameters, including changes within the renal biopsy and changes in complement biomarkers, will be evaluated. In addition, in the study, there will be an evaluation of the safety profile in complement-mediated disease. So to achieve a broad label, the study will include C3G and IC-MPGN, adults and adolescents and posttransplant as well as disease in the native kidney. Thank you very much. I'll go through the key takeaways, sorry, on -- if you just go back one slide, I beg your pardon. So these are the key takeaway messages. IC-MPGN and C3G are rare, chronic, complement-mediated diseases resulting in kidney damage and failure and important to emphasize, no approved therapies. I've talked about the excessive deposition of C3 breakdown products, which are the key driver of much evidence to support this -- of disease. And EMPAVELI achieved a proof of concept in C3G by demonstrating this reduction of 73% in mean proteinuria at 48 weeks. And I've mentioned that the Phase II study and Phase III time lines, as indicated there. Thank you.

A huge thank you for joining us from London. It's always that moment where you keep your fingers crossed that the connection works. So thank you. With that, we're going to transition over to neurology. And I'm going to welcome Dr. Angela Genge, who's going to talk to us about the EMPAVELI potential in ALS. So with that, I will hand to her.

And I'm a neurologist. And I currently am the Executive Director of the Clinical Research Unit at the Montreal Neurological Institute and run the ALS center of excellence at The Neuro, which is a part of McGill University. Next slide, folks. So I'm going to talk to you about amyotrophic lateral sclerosis, also known as ALS. It has become quite familiar to people as a result of the ice bucket challenge a few years ago, but let me fill you in on some of the more important details of this disease. It is considered a rare disease. It is a fatal neurodegenerative disease and is characterized by loss of both the upper and lower motor neurons. And in fact, both have to be evident in order to make the diagnosis. Currently, about 75% of patients present with a peripheral weakness, so either an arm or a leg becomes weak, and about 25% present with difficulty in swallowing or speaking. These presentations can be very innocuous. They are painless. And this disease actually affects, at any given point, 225,000 people worldwide. About 90% of those have a sporadic form of the disease. The disease is tragic in that in our current level of therapies, it is typically fatal 3 to 5 years from diagnosis. It -- as I mentioned, it is painless. It is innocuous. It can present with a change in your golf game. It can present with a slur in your speech that sounds like you have been drinking slightly too much. Both of these are very common presentations of this devastating disease. Also importantly, there's no current specific treatment targeting neuroinflammation, which is believed to be one of the underlying mechanisms by which the upper and lower motor neurons die. Next slide, please. So why we're talking about it today is really based on some really solid evidence that complement-mediated neuroinflammation is actually a key driver of the neurodegeneration that occurs in ALS or Lou Gehrig's disease. There is extensive evidence through multiple studies that the complement activation plays an important role in this disease. And part of this evidence, in fact, is demonstrated elevation of C3 levels in not only the serum but in the brain and spinal cord compared to unaffected controls and some disease controls. Individuals with ALS are known to have high activated C3 specifically at the neuromuscular junction. You can see the cartoon of the neuromuscular junction in the bottom right corner, and this activated C3 causes destruction of the neuromuscular junction as part of the cell death pathway that's activated in ALS. The current studies support this, both in the serum of living patients and in some experimental models. To look more closely at the disease, we have this electron microscopy photos of complement C3 levels deposited at the neuromuscular junctions of patients living with ALS. These are photos of the neuromuscular junction. On the left, you can see the control. Pictures on the right, you can see patients with ALS. And the green really highlights the degree with which C3 complement and its products such as C3b can be found at the neuromuscular junction in these patients with ALS. These contribute to the neuroinflammation and ultimately, the death of the motor neurons. What we have in EMPAVELI is a drug that can directly target C3, inhibit it and, therefore, slow the disease progression in ALS. We believe that by targeting C3, we can disrupt the cascade, thereby preventing the neurodegeneration and the neuroinflammation and, in fact, also preventing the formation of the membrane attack complex, all of which are destructive in patients with ALS. EMPAVELI is currently in a clinical trial. The trial is MERIDIAN. It's a Phase II study in ALS that is taking patients with sporadic ALS and treating them twice a week with EMPAVELI. More specifically, the patients are screened to have ALS. The patients simply have to be adult patients over the age of 18, and the study actually consists of twice-a-week treatments in a 2:1 randomization with placebo. The active phase of the study is 52 weeks or 1 year with an open-label extension planned in which all patients who remain in the study have the option to go on EMPAVELI. The primary end point is one that is strongly suggested by the FDA for pivotal trials and proof-of-concept trials. It is referred to as the CAFS or the Combined Assessment of Function and Survival. And this particular primary end point takes advantage of our most well-known end point, the ALSFRS, which is a functional rating scale that we use to determine disease progression. And secondary end points, which are very important, will include muscle function end points, a pulmonary function test, handheld dynamometry for strength testing, quality of life scores. And obviously, we will be tracking the ALSFRS. And finally, there will -- there are components in our exploratory end points that include markers of complement levels and complement function. With this program, we hope to prove that the complement, particularly C3, is not only a targetable component of the complement system. But in fact, by targeting C3 and inhibiting C3, we actually will be able to decrease neuroinflammation in these patients with sporadic ALS and ultimately cause a slowing of progression of the disease and an improved survival, as we will measure with the CAFS. The key takeaways from the ALS program include the following: we know that it has a large unmet need with an urgent need for treatments that slow progression and improve the length of time people live. We certainly believe, based on our evidence, that we have complement activation and elevated C3 levels, that this is a target that can be effectively controlled. And that by controlling complement activation centrally at the level of C3 with EMPAVELI, that we have the potential to slow the progression of ALS with both the central and peripheral evidence of C3 activation. And the good news is we expect to finish enrollment by the end of 2021 and complete the placebo-controlled portion of the trial within a year following. Thank you for your time.

Dr. Genge, thank you so much for joining us and taking us through our ALS program. So with that, I hope you guys are keeping up as we go through rapid fire. We're going full circle back to hematology where we'll end out hearing from our key opinion leaders with Dr. Bruno Fattizzo, who will talk about 2 indications in hematology starting with cold agglutinin disease. So with that, I will hand over to him.

Hello. I'm Bruno Fattizzo, consultant hematologist and clinical researcher at the Policlinico Hospital of Milan, Italy. And I have a specific interest in immune hematology, particularly in autoimmune hemolytic anemias. And today, I'm going to talk about cold agglutinin disease. In the next slide, we see that cold agglutinin disease is a rare and heterogenous disease characterized by the production of autoantibodies directed against the antigens on the surface of the erythrocytes. These autoantibodies are usually more active at low temperatures, lower than body temperature of 37 degrees. And they are usually of IgM class. IgM are pentameric and are, therefore, able to activate the complement cascade and to induce both intra- and extravascular hemolysis. Symptoms of the disease include hemolytic anemia and fatigue, transfusion requirements in a proportion of patients and cold-induced disabling circulatory symptoms. And also, patients with CAD have an increased risk of thrombosis. And in the next slide, we see the results of the Phase II PLAUDIT study that evaluated the efficacy and safety of pegcetacoplan, which is a C3 inhibitor in patients with cold agglutinin disease and also in patients with warm autoimmune hemolytic anemia, whose data are not presented in the slides. This is particularly important since in cold agglutinin disease, we do not have a standard of care. And patients are usually handled with steroids that are effective only at high and acceptable doses of rituximab that is not labeled in the U.S. nor in Europe. And that is effective only in a proportion of patients and mainly induce partial responses. So the PLAUDIT study evaluated the efficacy and safety of EMPAVELI, given at a daily dose of 250 milligrams per day subcutaneously versus another arm of the trial, where EMPAVELI was given at a daily dose of 360 milligrams per day subcutaneously. 13 patients with CAD were enrolled. And the inclusion criteria were the diagnosis of CAD, the presence of hemoglobin levels less of 11 grams per deciliter, the activation of hemolysis as measured by hemolytic markers such as LDH and the evaluation of direct antiglobulin test that had to be positive for the C3 fraction on the complement. The primary end points were safety evaluation but also the change in hematologic parameters, including hemoglobin and hemolytic markers and the improvement of quality of life as measured by the FACIT-fatigue score. And in the next slide, we can see from the graph down here that shows the trend of hemoglobin levels during the trial, that EMPAVELI was able to induce an amelioration, an increase of hemoglobin levels as soon as the first -- as of the first week of administration. That was maintained along the whole study period, up to 178 days of treatment. Additional efficacy outcomes were in the obtainment of the transfusion independence that was reached in 77% of patients, the amelioration of hemolytic markers that was consistent with the hemoglobin increase and decrease of hemolysis and also the improvement of quality of life, as measured by an improved -- an improvement, an increase of FACIT score by 7.7 points from baseline until week 24. Safety profile was very good, and patients were -- did tolerate well the therapy with pegcetacoplan. And all 13 patients experienced at least one treatment-emergent adverse event, but most of them were grade 1 or 2 such as reactions at the site of injection. But no patients experienced a severe adverse event leading to discontinuation of pegcetacoplan that was considered related to pegcetacoplan. So we can conclude that cold agglutinin disease is a chronic and severe blood disorder with no approved therapies nowadays. EMPAVELI may be able to control hemolysis in cold agglutinin disease by controlling the complement activation, both the lectin, the alternative and the classical pathway of the complement, which is, of course, the most important in this disease. EMPAVELI demonstrated meaningful efficacy in increasing hemoglobin but also decreasing hemolytic markers and was well tolerated in the PLAUDIT study. And also, the drug had a good safety profile but also was able to improve the quality of life of our patients. Finally, Sobi is the company that is going to initiate that Phase III study in the second half of the 2021. And now let's move to another topic, which is the hematopoietic stem cell transplant induced at thrombotic microangiopathy that we will call posttransplant TMA. And on the next slide, we will see that C3, so the complement fraction 3, plays a critical role in the pathogenesis of transplant-related TMA. When being subjected to a hematopoietic stem cell transplant, patients with hematologic disorders usually experience many complications, including infections and also are given a variety of drugs, including immunosuppressants. All these stressors may contribute to the development of a novel inflammatory state with overactivation of the complement cascade that may induce endothelial damage, blood clotting and organ damage. This process may result in posttransplant TMA, which is a multisystem disease characterized by microangiopathic hemolytic anemia, consumption of thrombocytes and microvascular thrombosis. Patients who develop organ damages as a result of a transplant-related TMA usually have high mortality rates. And as we mentioned before, C3 is believed to play a critical role in posttransplant TMA. And also, it has been shown that patients developing posttransplant TMA have high levels of the complement fraction C5b, which indicates a terminal activation of the complement cascade. And in the next slide, we can see that posttransplant TMA is associated with a very poor outcome. In fact, the disease is difficult to be diagnosed and to be recognized in the clinical practice. And therapy today only relies on supportive treatments. And in the graph on the right, we can see that patients with hematopoietic stem cell transplant developing posttransplant TMA have a particularly dismal outcome with high mortality and reduced overall survival as compared to patients not developing TMA. And the incidence of posttransplant TMA is recognized to be about 40% for all hematopoietic stem cell transplant with up to 50% of patients developing TMA experiencing a severe disease. And if the patient develops a severe posttransplant TMA, then the mortality rate would reach 90%. So the disease is a true unmet need. And in the next slide, we have an overview of the complement cascade that starts with the classical pathway activation or lectin pathway or alternative pathway. Both of -- 3 of these 3 ways of activation of the complement cascade will usually result -- converge on the activation of the C3 convertase. The C3 convertase is able to produce both the C3a, which is an anaphylatoxin that induces inflammation, but also C3b fragment of the complement. And this C3b is able to precipitate on the surfaces of the organs and the cells and cause organ damage and blood clotting if it precipitates, for example, on the surface of the endothelial cells. Also, the C3 convertase is participated to the formation of the C5 convertase, which is downstream complement activation. C5 convertases would again produce the C5a, which is another anaphylatoxin that could further increase the inflammatory state, but also C5b that is able to activate the membrane attack complex, that is the final activation step of the complement that [indiscernible] is able to induce blood clotting and organ damage. These 3 pathways, the classical, the lectin and the alternative one, are overarching in patients with posttransplant TMA. So that the inhibition of complement, particularly the crucial point of the C3, would be the best way to control the other activation of complement and overinflammatory states observed in posttransplant TMA. And in this sense, EMPAVELI has the potential to control the complement cascade at the level of C3, blocking all 3 activation pathways of the complement and stopping the inflammation, blood clotting and organ damage typical of the disease. So the final points are that the posttransplant TMA is a multisystem disease associated with high mortality rates and difficult to be diagnosed and recognized in the clinic with -- and managed as of today only with [indiscernible] measures. EMPAVELI has the potential to control the extremely overactivation of complement and the overinflammatory state by targeting C3, so the final converging points of the 3 complement activation pathways And the Sobi is the company who is expected to initiate a potentially registrational Phase II study in the second half of the 2021. And I thank you for your attention, and I give the word to the Apellis company.

Thank you so much to Dr. Fattizzo for his last 2 presentations. So there's a lot of information on this slide, but I'm going to do my best to recap it for you. So I think what you've heard over the course of the last few presentations is the potential that EMPAVELI has to transform the way the complement-driven diseases are managed. What we also strive to achieve is not only a rapid and parallel development plan, but one that is done in collaboration with the key stakeholders. So we work closely with KOLs, with advocacy groups, with patients and with payers to ensure that the design of our studies is closely matching what is expected and will ultimately improve the outcome of these patients. What you will also have seen from the presentations is the need to build on that with real-world evidence and best-in-class patient experience. So by bringing those elements together, we believe that EMPAVELI will add significant value to the health care system and also to the health care community living with and treating these diseases. You'll have seen in the presentations prevalence numbers for each of the diseases that we went through. What you see here is the number of patients that we believe EMPAVELI will directly impact and benefit. What you see collectively over the course of these indications is a total of just over 34,000 patients in the U.S. that we believe due to that comprehensive control of complement that was nicely explained by each of our speakers today as to why that is the best route for these diseases, that with that, through an innovative and mindful and thoughtful design to our studies, will result in a set of outcomes that is meaningful to each of these disease areas and patients. You'll see also some of our key milestones at the bottom to watch out for throughout the course of this year and towards the end of the year and into next year. Okay. So with that, we're going to pivot to the last part of our strategy and really round out what we believe is already a very positive patient experience with EMPAVELI. You heard from David earlier in the day that patients find it very easy to start on EMPAVELI, but we don't want to necessarily stop there. We want to build and enhance on that experience to make sure that we are truly meeting the needs in the best way that we can with these patients. So with that, we're going to look to innovate and develop patient-centric improvements to our device through dosage and administration. We're going to look to reduce the dosing frequency of EMPAVELI and also how we can expand with new assets into our portfolio, which will lead us into new indications. So I will start talking about how we're going to enhance that device experience. So in partnership with Enable Injections, we are working on bringing to market a patient-centric device. What you'll see from this device -- and we'll show you a video in a few minutes that I think highlights it much better than I can do a job in terms of articulating it. But what we're seeing in terms of movements within the health care system and environment that, that patient experience and beyond the medicine offerings are becoming increasingly important to patients. So at Apellis, we feel it's fundamentally important to also be on the cutting edge of that innovation and ensuring that we're meeting the needs not only from a medicine viewpoint but also from our other services and offerings that round out that patient experience. What we love about the Enable device, and we heard this from patients also, is that it's more closely aligned to what they are looking for, but also, and importantly to us, that the features that trigger a strong sense of adoption and adherence score extremely highly with Enable. So as I mentioned, I can't do it justice with my words. So I'm going to show you guys a quick video, which I think highlights the simplicity and the ease of the Enable device. [Presentation]

Okay. I always feel that reminds us, I guess, as excited about the thought of this device being available to patients. Our aim in the U.S. is for our PNH patients to have access as early as the end of 2022. And then obviously, for our other systemic indications, the device will also be available. So with that, I'm going to hand over to Lukas Scheibler, our Chief Innovation Officer, who will talk us through our other enhancements to our rare disease program.

Thank you, Vicky. So in order to further improve the patient experience for EMPAVELI, for pegcetacoplan, we would like to reduce the treatment frequency from twice a week to maybe as little as once a month. And in order to do that, we decided to combine EMPAVELI with an siRNA, silencing the expression of C3 in the liver. When you look of the reason why we need to dose EMPAVELI today twice a week, it's mainly driven by the liver that produces about 1 gram of C3 every day. And this 1 gram of C3 needs to be inhibited, and that obviously needs a substantial amount of inhibitor just to achieve that. If you can reduce the amount of C3 that is produced and secreted in the liver to a lower amount, you can extend the treatment posology of EMPAVELI or potentially reduce the dose of EMPAVELI to achieve the same treatment benefit as we currently see with the drug which we commercialize. Now siRNAs can do that. Silencing RNAs can do that. They're designed to silence the expression of proteins in cells. And if you pair them with a sugar, a specific sugar called GalNAc, you can actually easily deliver them directly into the hepatocytes of the liver. And you can target specifically the liver and silence expression of proteins in the liver. This general approach of targeting siRNAs to the liver has been approved in at least 3 different products and is in multiple products in clinical development right now ongoing, as you can see here on the bottom. We at Apellis, we have started to make siRNAs that target the C3 mRNA and that silence the production of C3. What you see here on the left side on this slide here is we took one of these GalNAc-modified siRNAs which are targeting the liver, and we dosed monkeys with them. And what you see on the left side is liver biopsies where we quantify the level of mRNA for C3 we find in the liver over the course of time. And as you can see, we get a really robust inhibition of the mRNA levels for about 90 days. And afterwards, the levels are coming back. Corresponding to this mRNA level, we see the levels of C3 in circulation shown on the right-hand side. And you can see a dose-dependent reduction of C3 circulating in serum in the blood stream once dosed with the siRNA. And again, a single dose of this siRNA lasts for about something like 90 days in these monkeys. And afterwards, you get a recovery to normal levels. In summary, we get more than 99% reduction of mRNA levels with the highest dose, and we get over 90% reduction of the circulating C3 levels with the highest dose. Now we have also measured in these monkeys the remaining hemolytic activity of the remaining complement components, including C3 in the blood of these monkeys. And we see a pronounced reduction of this hemolytic activity but not a complete inhibition of the hemolytic activity. And that together gives us the information that we need to combine this siRNA with EMPAVELI to have complete control of the complement cascade as needed if you want to treat diseases such as, for instance, PNH. This has been observed also by others, and here is some data from one of the pioneers of siRNA, Alnylam, who made siRNA-targeting C5. What you see in the top left corner here is their results, their published results about the reduction of circulating C5 in the blood. You see here as well a pronounced reduction of protein, but it didn't translate to a complete control of hemolysis here in these monkey studies. In the middle, you see their results. When they used this particular siRNA and dosed humans with it, they got a nice reduction of circulating C5. But they couldn't really control as a monotherapy PNH completely as observed with -- in their LDH levels. However, when they combined this siRNA with eculizumab, then they can actually reduce the treatment frequency required for eculizumab and control the disease to the extent possible you can with a C5 inhibitor. And so we intend to use the same approach, but we intend to go after C3 such that we can control extravascular as well as intravascular hemolysis. So in summary, what I have shown you is we believe that silencing C3 in the liver offers the potential to reduce the treatment frequency of EMPAVELI maybe to once every month. We have started to make siRNAs. Our lead products currently reduce the expression levels by more than 90% of circulating C3, and it lasts for more than 3 months. And this -- together, these results support our hypothesis that we can reduce the treatment burden or the treatment frequency of EMPAVELI to maybe once every month, and we plan to submit the IND next year. With this, I would like to switch to the next program we started off. It is about oral complement inhibitors. We have started to work on oral alternative pathway inhibitors. As you can see on the left, we only hit one activation path of the cascades. Our intent is to use these type of molecules for diseases which are mainly driven by the alternative pathway and may not require a complete control of the complement cascade as you can achieve with a C3 inhibitor that basically inhibits everything. We have made initial molecules on this with awesome bioavailability both in the IV as well as in the oral form. And we have compared these molecules to Novartis' lead compound, LNP023. And you can see that our molecule in this [indiscernible] functional assays, is more active than the Novartis compound. As I said, we plan to use this type of inhibitors in diseases where the alternative pathway plays a role, where maybe not the complete control is required. And one of the first diseases we picked that we want to go after is early or mild C3G disease, as we discussed just before, where maybe in this mild form, the patient is willing to compromise a certain level of efficacy, which you could achieve with EMPAVELI versus the convenience of oral dosing without the need of injections or infusions. And with this, I hand back to Vicky.

Thank you, Lukas. Okay. So just to quickly wrap because we covered a lot of information over the last hour or so, we covered really 3 main topics. So the first one, we talked about how we're setting that foundation and tone within PNH with those very early indicators of the impact that EMPAVELI is having on the U.S. market. Secondly, we talked about how we will expand our list of indications and disease areas, specifically focusing on diseases where we believe that comprehensive control of complement that EMPAVELI offers will result in improved outcomes and meaningful improvements in quality of life for patients. With those aspects in mind, we believe that EMPAVELI has blockbuster potential but importantly is transforming the lives of patients with complement-driven diseases. We also talked about how we will continue to improve on the patient experience that we currently have, which is great. But we want to take that bit step further improving on not only how to administer EMPAVELI with the Enable device but looking at ways to reduce the dosing frequency and then expanding beyond EMPAVELI with new assets and future indications. So with that, I'm going to ask the current speakers -- or the previous speakers that we had, sorry, to rejoin me on stage. And we will also bring our key opinion leaders back on as well so they can address any questions you may have for them. Okay.

Now we're going to argue who's having chairs. Okay. Okay. So while we bring out a couple of extra chairs up, I'd love to start with any questions that you guys might have in the room to either our Apellis folks or to our key opinion leaders.

It's Steve Seedhouse from Raymond James. A couple of questions. Maybe I'll just go one at a time because they're on different programs. First, in renal, the -- you guys did not see an eGFR improvement. And I'm just curious if you think that's a function of the type of patients you enrolled, heterogeneity? Or if that's just what we should expect in a pivotal study? And I'm also curious if you look at a biopsy posttreatment, do you see changes in the C3 deposition in the kidney?

So do you want to take a pass and then we can ask Dr. Pickering?

I think Dr. Pickering is the best to answer that. So Dr. Pickering, I don't know if you heard the question?

Yes. I did. I think the time scale with this condition, it would be not sensitive enough to pick up changes in eGFR. These patients have progressive disease, but the decline over that period would be relatively slight. And yes, I would expect in biopsy features to start to see reduction in C3 deposition. That would be certainly an encouraging thing to see. However, it needs to be borne in mind that from experimental studies, some -- even when you switch C3 activation off in experimental animals, you can see long-standing C3 staining lasting many, many months, which can confuse the issue, okay? So it wouldn't necessarily be that you would see complete resolution of C3 where you'd expect to see a reduction.

And I could maybe add one other thing to that, Dr. Pickering. In PNH, for example, right, where we see the efficacy of the drug occur very quickly after administration, when you take the red blood cells out of circulation and you measure on flow cytometry the C3 deposition, it goes away not over 1 or 2 weeks but over the course of 3 to 4 months. And it was one of the most fascinating observations we had in the PNH studies early on because what it is really is that C3 that is there never goes away, except now these red blood cells don't get removed anymore because there's no continued accumulation. And there's new red blood cells come into circulation that do not accumulate any C3. That is what that flow cytometric pattern really shows. So to Dr. Pickering's point, once you have -- and by the way, we don't have -- that is the pathological data available yet, but you should expect that to take some time to resolve.

Okay. I'll maybe pack 2 together because they're quick. So on the launched Enable device, it was a great video, and it was 5 seconds long. But I'm curious how long the actual infusion would be for that device. And then the second question is on the oral alternative inhibitor. What is the molecular scaffold of that? Is it also a cyclic peptide or is it -- is this from a high throughput screen? Or what are you actually developing?

So on the first one, shall I take -- you want to say it?

Either, either.

Then you go.

Okay. So with regards to Enable, so right now, we're in the process of finalizing kind of the data that needs to be done for submission and approval. But we're anticipating around the kind of 20-minute mark for that infusion. I think what is of note maybe to call out with Enable if it isn't implied, it is just the one device that is required for the patients, whereas given the -- some of the other competitors will require to.

The small molecule is a small -- the oral molecule is a small molecule, which is originated from a screening effort.

We had an amazing chemist in the company, Dr. Mark Orme, who unfortunately passed away but who developed that or created that drug about 1.5 years ago.

Something like that.

Yes. We started -- the trick was really to get the assay running. And then once we have the assay running at the hits and then from the hits to its lead.

Any other?

Joey Stringer from Needham. Two quick ones, one on PNH. You gave some early metrics on the payer mix, I think around 50% commercial. Do you sort of expect that to remain relatively stable as the launch progresses? And then the second one is on ALS. What's considered a clinically meaningful change in CAFS score? And can you maybe remind us on some of the inclusion criteria for that score? And is that representative? Or what percent of the sporadic ALS patient population that would be representative of?

Okay. So maybe we can hand the PNH question to David, and then I'll go to Dr. Genge for the ALS question.

Sure. Thank you. So yes, we will see the 50% commercial patients and the 50% that are in government stayed pretty consistent. The way we've gotten to that is through current claims data with patients that are on product for C5. So I don't anticipate that it will change too much.

Okay. Dr. Genge, did you catch the ALS question?

Absolutely. So there are 2 different components to the question. One is related to what patients would be eligible. And really, all patients who are sporadic and have clinically identified ALS, we'll put aside our ranking system because clinically proven ALS is actually probable by El Escorial criteria. And the primary outcome measure, the CAFS, combined measures of function and survival, is what the CAFS is. But the key 2 components, one is survival, obviously. But the other component is the ALSFRS, which is the ALS Functional Rating Scale, and that is a very much validated functional rating scale that we've been using as a primary outcome measure for close to 20 years now. It really assesses actual function. So it has fine motor, gross motor. It has respiratory function. It has bulbar function all included in the scale. The meaningful -- what is accepted as clinically meaningful is a slowing of progression by between 25% and 30% of the ALSFRS. The CAFS is a little bit more difficult to identify what's clinically meaningful simply because it is a combined score. But we're looking at a percentage around 25% slowing of progression to be considered clinically meaningful. And that has been upheld through the most recently approved drug for ALS in the U.S.

Thank you.

This is Madhu Kumar from Goldman Sachs. So a follow-up question for Dr. Genge based on something that Cedric mentioned a few minutes ago. This observation that the C3 accumulation and turnover is more -- at least in the red blood cell, is a function of kind of new accumulation as compared to prior accumulation. How do you think about that in terms of, as you mentioned just now, that the enrollment in sporadic trials is based on clinically defined criteria? What gives you confidence these people haven't had so much C3 deposited at the neuromuscular junction that further intervention will be able to kind of ameliorate the pathology at that site?

That's a great question. The strongest evidence we have is in -- which is combined evidence across multiple different programs, is that you can see a stabilization of the loss of normal architecture of the neuromuscular junction when you inhibit the complement pathway. This has yet been -- to be proven in the clinical programs. But certainly, the understanding is that if you treat patients within our inclusion criteria, which is in the earlier stages of ALS, they are not on a ventilator, they don't have a gastrostomy, that within the process of neuroinflammation, once you control that C3 level by causing inhibition of C3, that you can have a direct effect on the neuroinflammatory process. Because the neuroinflammation is considered to be happening across the different upper and lower motor neurons, the effect may be, in fact, stronger than we expect because much of the clinical effect is due to concomitant upper and lower motor neuron dysfunction. So if you're controlling the C3 activation, you're actually controlling the disease and the neurodegeneration at 2 different levels and protecting the synapses, both centrally and in the spinal cord.

Any other questions? And I think we have one online.

Yes. So we have a question from the fans at home. "How do you view the competitive landscape of treatments for CAD?"

Okay. So Dr. Fattizzo, did you manage to catch the question on CAD?

Yes. Thank you. So for years and years, we've been treating CAD with steroids and steroids and steroids, experiencing all the side effects of this therapy. And we finally understood in the last 10 years, more or less, that CAD is a different disease as compared to her sister, [ warm antibody ] hemolytic anemia. And we finally understood that steroid is not the answer for this disease. And also, sadly, we saw that also rituximab is not the answer for this disease because most patients would relapse earlier after the end of rituximab, of course. And they end up being treated again and again with rituximab and again and again with steroids even if we know that these treatments are not so effective. So complement inhibitors are, of course, one of the answers for this disease. But what we learned from both these trial and also other trials with complement inhibitors, for example, the C1s inhibitor sutimlimab that has been published recently, and that is affecting also in more or less half of patients with cold agglutinin disease, is that this disease is a chronic complement cold agglutinin disease. But this is a sort of multifactorial syndrome, where we have both hemolytic anemia but also inflammation, chronic inflammation and risk of thrombosis. So probably targeting only the classical pathway of the complement, for example, by C1s inhibitor with the [ tran-sutimlimab ] is not the exact answer to a disease that has much inflammatory state and complement activation -- chronic complement activation. So I -- in my view, a drug that is able to target the component cascade in the middle where all the 3 pathways of the complement cascade that converge could better control hemolysis in this disease. And the other thing is that this possibility to have an easy device to be used by the patient could be made in the future, the option -- an option for use on demand of complement inhibitors in this disease because it is true that this disease is chronic, but it is also true that its nature of being activated by, called it, the temperature makes it more active usually during cold seasons. And our patients experience most crisis during cold seasons. So this is one observation. And the other thing that I would like to point out is that, for example, we have many patients with cold agglutinin disease that have to avoid cold exposures. And for example, they need to avoid going to -- climbing or, for example, diving. And all these headaches may be positively allowed in a patient who is under complement inhibitors. So it's not excluded that in the future, these drugs would significantly ameliorate patient convenience. But also, they have the quality of life and also they -- how they live their daily lives.

Thank you. Okay. I think we have time for one more question. So I see one here in the room. Or do we want to take one from the phone? Over here.

Eliana Merle from UBS. Just a question on C3G and the renal opportunity. You mentioned you have a preclinical oral factor B targeting sort of the more mild presentation of the disease. Can you elaborate a bit how you're classifying mild versus severe and how you're thinking about where and what patients full C3 control would be necessary through all of the complement pathways versus where the alternative pathway control would be sufficient?

Yes. I think we'll probably take a combination approach to this one. Cedric, do you want to start? And then we can go from there.

Yes. I think it's an excellent question. Thank you so much. The notion there is really that if you are -- I mean this disease often emerges in young -- in kids or in adolescents. We're doing a subcutaneous infusion, obviously, something that is very unpleasant to do. And the path to end-stage renal failure or to real kidney damage can take quite a bit of time, I mean, can take 10, 15 years. We really started thinking about this actually in the context of our own proof-of-concept study in C3G, where we had a student at the university self-aware about having the drug product in the fridge, et cetera, and where he said, "If you have to trade a little bit of efficacy for the benefit of having a pill that you can afford to forget to take once in a while, that may be something very attractive, particularly in that disease." Note that it's not just in that form of C3G but also in other indications that we'll talk more about in the future. But where the common denominator is where comprehensive complement control is not needed, we think this could be a very attractive option. I don't know, Matthew, if you would like to add something to that.

No. I'd agree with what you said. I mean it is a very heterogeneous disease, and it's just difficult without these trials to estimate the degree of inhibition that one might need to have a clinically impactful effect. It may be that we need to modulate complement rather than achieve total blockade. You contrast the situation most starkly in a patient presenting with acute atypical hemolytic uremic syndrome where you really need to achieve rapid complete inhibition at the level of C5. It may be in C3G that modulating C3 and achieving 70%, 80%, 90% inhibition will be sufficient.

Thank you. Okay. So with that, that concludes our coverage, ratify our whistle stop to our -- of our rare disease franchise. I thank you for your engagement and your questions. I want to say a huge thank you to our key opinion leaders that joined us today and for all of our Apellis speakers. Thank you. So with that, lunch at 2:00. So I believe there are box lunches outside if you guys want to grab them and come back, and we are due to restart 2:30. Thank you.

We're just getting started.

Caffeine up. [Break]

Very good. All right. I hope you all had a chance to grab your lunch package. And let's get going again. We are switching gear now from the rare diseases, and we're going into brain-active complement inhibitors. You may ask yourself why the brain, why the CNS. And for us, one of the key elements is really that we consider the retina as part of the brain or the brain as part of the eye as however you want to look at it. And the results you are very much familiar with and we have shared with you in the past and which we will see much more afterwards as well, the results we have observed in geographic atrophy can be translated into generally the CNS as the processes which are the biochemical processes, which are underlying diseases like geographic atrophy but also Alzheimer's disease and all other neurodegenerative diseases are the same neuroinflammatory diseases, C3b deposition, activation of microglia and so on. And with this, I would like to hand over to Dr. Genge, who is going to give us an overview of complement in CNS. Thank you.

Thanks again. So I'll be sharing with you the support -- the research and support of the role of C3 in neurodegeneration. Next slide, please. And really to give you an overview, I think this slide really points to the weight of the body of evidence. We now have multiple preclinical studies in multiple disease areas suggesting that C3 inhibition is neuroprotective in aging and in neurodegenerative diseases. And we have evidence across the spectrum. So in human, Alzheimer's disease brain, in PSP or supranuclear palsy, in traumatic -- chronic traumatic brain injury, in multiple sclerosis and in even some rarer diseases such as Creutzfeldt-Jakob disease. We have ongoing evidence that this activated microglia and increased levels of C3 are a problem in these disease areas, particularly in aging, and that C3 inhibition such as what EMPAVELI provides us is neuroprotective. Next slide, please. To remind everyone, in fact, it was not always the case that C3-mediated pathways are negative. In fact, in the developing brain, synaptic pruning is a very important pathway to reach the mature brain. And in those periods in our growth and in our life in which we require synaptic pruning, C3 in conjunction with microglia, lead to the mature brain that characterizes the adult brain. Unfortunately, in neurodegenerative disease, this balance becomes destroyed or misled. And we've developed this reactive microglia and increased C3 levels that takes us from synaptic protection to neurodegeneration. Next slide, please. We have some evidence that this is actually very important in various forms of neurodegeneration. We have samples that, in fact, come from the CSF of patients with Alzheimer's disease in which we have elevation of both C3 and process proteins such as C3b and C3c. And these are increased in the CSF patients with Alzheimer's disease as compared to normal controls. The technique that was used is one that is becoming increasingly important, the Quanterix method with Simoa. And as you can see from the bars on the left, we have a significant difference in our levels with the increases in the Alzheimer's disease CSF. On the right, another set of very important experiments has demonstrated that when we knock out C3 in certain mouse models, we get the benefit of the protection and the protection of the synapsis. So with the C3 knockout model, we see synaptic protection compared to other disease entities, and that certainly again supports the concept that if we inhibit C3, we can actually have synaptic protection in the diseases we'd like to target. Next slide, please. So they've looked even more closely at several different pathways. And again, I think it's important to stress that we are dealing with multiple different rare neurodegenerative diseases on the left. And again, this is a comparison of -- demonstration that you have MR -- C3 mRNA elevated in multiple neurodegenerative diseases. The ones highlighted here are corticobasal degeneration and progressive supranuclear palsy, significant for the role of tau in neurodegeneration in these patients. And an important disease control, when they looked at Pick's disease, another neurodegenerative disease, they, in fact, did not see this C3 elevation in the mR -- C3 mRNA, which really provides some very solid evidence that what was seen in the CBD and the PSP patients was actually significant. On the right, the graph really demonstrates what happens when you knock out C3 in a mouse tauopathy model and that you can actually rescue the phenotype and rescue the pathology that you would normally see by providing this C3 knockout. Next slide, please. How far can we go? Well, we can go very far. These are experiments that were run in multiple sclerosis. So multiple sclerosis is one of the most well-known neuroinflammatory diseases, and we know that historically, it was always considered a disease of the white matter. However, we now understand that may very well be a primary gray matter disease. And in fact, one of the overarching issues now that we can treat the immediate neuroinflammation over the last 20 years is that we've had limited success with cognitive decline in patients with progressive MS. And these series of experiments demonstrate that we have an increase in C3 in patients with MS, both in the CSF and in the autopsied brain. And this would suggest that we're getting increased microglial -- activated microglial-led synaptic pruning, which in this case is a negative because we decrease the density of the synapses and we increase the CSF levels at the level of the synapse. On the right, we have an image showing the evidence of the cortical atrophy and cognitive decline in MS patients. So the potential here for a treatment that is as safe as EMPAVELI with no clear toxicity, no interference in the days currently of a pandemic, no real interference of natural immunity that can be seen in some of the other drugs that have been used for control of MS to date. So an opportunity really across many neurodegenerative diseases to have a positive impact on the disease by controlling neuroinflammation through C3 inhibition and, therefore, being synaptic protective and delaying the decline and loss of neurons across a wide spectrum of neurologic disorders. So if we go to the final slide. Next slide, please. Really, we have rationale at multiple levels. Earlier, I mentioned the importance of elevated C3 -- inhibition of C3 in motor neuron disease where the neurodegeneration is in the motor neurons. In this presentation, we've really focused on the other diseases that are prototypic of neurodegeneration, Alzheimer's, CBD, the tauopathies and the secondary MS effects of loss of brain matter. And what we see is that C3 regulation naturally is important for synaptic refinement, important for learning and memory in development throughout life. But when C3 dysregulation occurs, you get a loss of these synapses. You get dysfunction. And ultimately, you get cognitive and other declines and a loss of the appropriate neurons. So by looking at restoring C3 regulation, controlling the activated microglia that is part of the whole cascade and inhibiting C3, we're really looking at improving cognitive function across neurodegenerative diseases and improving and sustaining neuron viability by controlling this neuroinflammatory process. With this, I thank you and turn it back to the moderator.

Thank you, Dr. Genge. That was a nice introduction into where we could go with using our targeted C3 therapies for the treatment of multiple neurodegenerative diseases in the future. My name is David Eyerman. I'm the VP of Translational Medicine here at Apellis. And I'm going to walk you through some of our exciting progress in developing and emerging CNS pipeline here within the company. I'll note upfront that one of the large historical challenges of developing CNS drugs is getting said drugs across the blood-brain barrier. This barrier acts to protect the brain from various insults, in fact, inflammatory mediators like complement as well as the influx of various solutes and prospective drugs. A number of people have come up with a multitude of different ways to bypass blood-brain barrier. I'm not going to talk about those in depth today. Some of them are shown here on the schematic. I will note that as I walk through my presentation here, I'll tell you a little bit about ways we are trying to bypass or get through the BBB in order to ultimately get our drugs to the brain to treat some of the neurodegenerative conditions that Dr. Genge was just talking about. So here at Apellis, we are actually beginning the build of a multi-asset CNS neurology portfolio. I joined about 2 years ago, and what we're showing today is the culmination of some of that progress. We have a first-in-class brain-active C3 inhibitor that I'll tell you a great deal about today called APL-1030. It's a new novel asset completely separate from pegcetacoplan. We also have an emerging research portfolio of additional assets for the future that could allow longer durability of effect, perhaps better patient experience and/or, in the future, actually gene therapy modulation. I'll focus the initial part of this talk today on APL-1030, however. This is the lead asset. We are currently in IND-enabling phase with APL-1030. We have ongoing GMP manufacture, GLP toxicology studies and modeling and simulation to begin to predict our human doses. And we expect at this point in time to have an IND in the first half of 2022. So what is APL-1030? APL-1030 is a novel molecular entity. It's a C3 and C3b inhibitor, as you can see on the right-hand side of the screen. It binds to C3 and C3b and thereby inhibits the spontaneous breakdown of C3 but also the assembly of the C3 and C5 convertases. We designed this molecule -- or this protein, sorry, to specifically mimic the precedent and pharmacology of pegcetacoplan. APL-1030 is a 64-amino acid protein. It's highly water soluble, and it's highly thermo stable. We can make this protein via either recombinant or synthetic manufacture. The latter allows us to make this more quickly for early-stage clinical trials. The other advantage of APL-1030 that we see is that the C- and the N-terminus are available and accessible for modification without impact on its biological functions. Thereby, we can make conjugated versions of APL-1030 or its brother or sister molecules in the future. This can allow us to actually make multivalent, multipharmacology ligands, attach ligands that can target APL-1030 to specific tissues of interest and in the case of what we're doing in the CNS neurology space, also create radiopharmaceuticals. APL-1030 will be delivered in our initial clinical studies via an intrathecal route of administration. To do this, we'll actually use an infusion pump system that's been used historically for the treatment of pain and spasticity and is approved here in the United States. This will allow us to produce a constant infusion of APL-1030 into the CSF space. And this allows us to utilize the more lax CSF to brain barrier to actually allow entry of APL-1030 into the brain. We've done a series of in vivo pharmacokinetic and pharmacodynamic studies with APL-1030 in rats and nonhuman primates, which are -- which were designed to mimic the infusion paradigm that we'll ultimately use in the clinic. We've seen a number of positive things from those studies, good tolerability and high brain concentrations in 5-day intrathecal pump infusion studies in rats. Additionally, we've shown that APL-1030 actually enters the brain interstitial fluid in rats. This is the compartment where we believe APL-1030 will be active ultimately. And we now have nonhuman primate data, which suggest significant brain entry as well as pharmacodynamic effect in nonhuman primates. I'm going to walk you through that data in detail here. The nonhuman primate study with APL-1030 utilized 4 dose levels of the drug infused over the course of 5 days into the intrathecal space. You can see on the left CSF levels of APL-1030 achieved, and on the right, plasma concentrations of APL-1030 achieved during that nonhuman primate study. We saw a number of things that were favorable during the study, including dose escalating exposure of APL-1030 in CSF, up to approximately 500 micrograms per ml. [ EG ], we achieved very, very high concentration in CSF, and the protein was still well tolerated. Steady state in CSF was achieved within approximately 8 to 24 hours post infusion. In the half-life of the molecule, post-pump shutoff in a subset of animals was approximately 3 to 6 hours in CSF and 24 hours in plasma fraction. We believe the shorter half-life in CSF is primarily governed by a turnover of CSF in the monkeys of approximately 4.5x per day. Another notable observation from this study is that the plasma concentrations are approximately 10- to 15-fold lower than CSF concentrations. We believe this again to be driven by simple turnover of CSF into the blood fraction. It's also notable in this study that while data is not shown here, the target engagement measuring C3 breakdown was achieved with all dose levels of APL-1030 in CSF, whereas in plasma fraction, we saw very mild and moderate inhibition of the complement system. So we believe our pharmacodynamic effect is selective to CSF and, as I'll tell you, brain. On the slide shown here, we have APL-1030 concentrations in various brain regions of the nonhuman primates following the 5-day intrathecal infusion in the Phase B animals. What we're showing here is a number of brain regions that are cognition-relevant brain regions, including subregions of the cortex and subregions of the hippocampus. The regions chosen here are specific because of interest because of some of the diseases that Dr. Genge mentioned earlier. The high-level take-home here is that we achieved dose-dependent escalation of brain distribution of APL-1030 across different regions with escalating doses of drug infused into the intrathecal space. Number two is that we had an a priori target tissue concentration that we wanted to achieve, that we predicted would produce a pharmacodynamic effect, both in healthies but also in a disease state. We achieved that target tissue concentration with either dose of APL-1030 in the cognition-relevant brain regions of interest. Following this, we examined pharmacodynamic effect in a number of cognition relevant brain regions from this study. Here, we're showing functional inhibition of C3 breakdown in multiple brain regions of the nonhuman primates following treatment of APL-1030. To do this, we measured the C3 breakdown product, C3a. As you can see here, the vehicle-treated animals had C3a levels of approximately 2 nanograms per gram across the different cognition relevant brain regions, the prefrontal cortex, tentorial cortex, the hippocampus CA1 and the hippocampus CA3. In contrast to that, animals treated with APL-1030 had C3a levels at or below the limit of detection of the assay. We're achieving greater than 80% decrease in C3a with either drug level of APL-1030 used in this study. I want to remind people, this is not a cell-based assay. This is not a rodent assay. These are nonhuman primates that have been treated with APL-1030. We believe the primate is a species that better predicts human pharmacology ultimately. This is very exciting data. And we believe the doses and the exposures that have been used here project to human dose levels in either healthy or disease patients that are readily achievable in our early phase clinical studies. So highlights on APL-1030. We believe that APL-1030 will be the first and only brain active C3 inhibitor to enter the clinic next year. APL-1030 distributes throughout the brain of the nonhuman primates. It inhibits C3 breakdown in the brain of these animals. We get greater than 80% reduction in C3 breakdown with the dose levels used. Based on Dr. Genge's talk, we believe that APL-1030 has the potential to treat multiple neurodegenerative disorders in the future. And we have an IND that's planned in the first half of 2022 for APL-1030. We have multiple IND-enabling studies ongoing now, GMP manufacturer, GLP toxicology modeling and simulation to project human dose levels. We believe this coming next year. With that exciting data on APL-1030, I'll take you to our emerging research pipeline. As noted above, we're developing additional assets here in the CNS neurology portfolio that could achieve longer posology reduced treatment burden, et cetera, in the future, or importantly, also perhaps that are specifically useful to specific CNS neurology diseases in the future. The first of those is developing a brain channel conjugate version of our small proteins. The Brain shuttle conjugate versions of our small proteins will ultimately enable us to deliver via IV or subcutaneous route of administration and get exposure of 1030 or similar protein products in the brain in the future. The brain shuttles use a trojan horse strategy and specifically utilize receptor-mediated transcytosis. There are others out in the ether who are working with similar technologies. We're aware of that. We acknowledge that. We are using a slightly different strategy here to enable future APL-1030 and similar small protein brain shuttle conjugate. Our initial nonclinical data is encouraging in this approach. In the study shown here, we conjugated our C3/C3b inhibitor to a brain shuttle moiety, using an end terminal conjugation and a simple linker. We -- not shown here is we did a bunch of pharmacology work demonstrating that we retain the activity of the pharmacologic moiety and retain the activity of the brain shuttle when we conjugate the 2 of them together. We then administered the brain shuttle conjugate to rats via IV route administration, and the data therein is shown on the right-hand side of the screen. Here, we show that we can get brain exposure of our brain shuttle conjugated C3/C3b inhibitors in the brain of the rats, we can achieve our target concentration again of approximately 1 microgram per ml in various brain regions of the animals following a single IV administration, of a modest dose, I should add, of the brain shuttle conjugate. It's a 10-milligram per kilogram dose. We're now doing further studies to evaluate the potential of this as a DC and also to extend these findings to higher species. And then lastly, I'll touch on quickly. The other expansion of the CNS neurology portfolio, which is ultimately to get to gene therapy type modulation of C3 in the brain. Our first exploration here is utilizing a gene therapy mediated secretion strategy to actually produce APL-1030 in the brain, because APL-1030 is made of all natural amino acids, we can do this. We currently have made plasmids versions of APL-1030 that allow us to secrete the ultimate drug product in various tissues. We're utilizing delivery devices that I think are familiar to this audience, lipid nanoparticles and AAVs to deliver ultimately our plasmid product to the brain. Again, our initial nonclinical data is supportive of this approach. On the left-hand side of the screen, we show that using a novel lipid nanoparticle system and an intrathecal route of administration that we could deliver our payload to the brands of rats, shown is lumbar intrathecal administration or cisternal administration. In the middle panel, we show APL-1030 secretion in human iPSC-derived brain cells, following exposure of those cells to the APL-1030 secreters. And lastly, on the right-hand side, we show actual protein production in the rat brain in 28 days following a single intracisternal administration of the 1030 secreting plasmids. This is very exciting. This is the next generation and where we are headed. Hopefully, today, I've conveyed the excitement around our emerging CNS neurology portfolio. We believe because of Dr. Genge's talk, and other data out in the ether that these molecules have the potential to treat multiple neurodegenerative diseases in the future by targeting C3 and limiting synaptic toxicity and microglial hyperactivity. APL-1030 is the flagship of this portfolio. It will be the first to go in demand. We target having IND in the first half of next year. Our preclinical data is strongly supportive of APL-1030, getting into the brain and producing a robust pharmacodynamic effect in the brain. We have additional assets that are coming that will expand our CNS neurology portfolio and potentially allow us to treat different diseases down the line. With that, I thank you, and I will turn it over to Cedric to talk about ophthalmology.

Thank you so much, David. Have you had enough yet because there's more. All right, the retina. And I've been told to make it a little bit faster because we're a little bit behind on time, and we certainly don't want to keep you longer than we have to. But I want to start just with the title here, be #1 in the retina. That is -- we don't put that there too as a cocky statement. This is really because geographic atrophy in the retina represents such an important problem for patients and for the physicians who treat it. It's easy when you are kind of thinking on a corporate scale or as investors around what does this represent in terms of numbers, et cetera. But if you really go down to it, one thing is to make a drug, another thing is to be able to change and transform how the retina practice works because today, there's not just this disease where patients have to hear that nothing is available to help them. There's also the patients with wet AMD who over the course of long treatment with anti-VEGF end up very often developing geographic atrophy as well. And right now, there is nothing available for these patients. So for those of you that were there 3 years ago, you may remember that we like quirky videos. And I mean we had to make another one. [Presentation]

So the retina, near and dear to our heart, this is where we have actually been working the longest of all the indications where we are. And what should we expect? So what we're going to talk about today? First of all is, of course, about Pegcetacoplan in geographic atrophy and intermediate AMD, then about APL-2006, which is a next-generation wet AMD product that we are having in development right now that I think you'll be very excited about. And then finally, about gene therapies for all forms of AMD. All right. What I thought I would do very, very briefly is, for those of you that had a chance to look at our R&D 2 hours that we did in January, on specifically the retina and geographic atrophy. We outlined the 4 key misconceptions that we believe are out there and that we believe are important to dispel for people that may be less familiar with the retina or geographic atrophy a complement for that matter. So very briefly recapping those and then we're going to go to the heart of the matter. First of all, first misconception, other complement inhibitors have failed. Why should pegcetacoplan work? This goes down to the biology of what we believe is at work in the pathology behind geographic atrophy. And very briefly to summarize, we think that because of various reasons, the C3 deposition that naturally occurs in the retina becomes a burden to these cells as we grow older. What does that mean? C3 binds covalently to the cell surface in the retina. And that covalently bound product needs to be continuously cleaned up by these retinal cells. As it turns out, the cellular mechanisms that we use to clean up that C3 product are the same mechanisms that these retinal cells need for the visual cycle for their job. And at some point, they start neglecting the cleanup of that C3 product, and then all s*** breaks loose, for like of a better term. So when you think about that particular mechanism, it is important when you target C3 not just to lower how much C3 gets deposited but that you lower it sufficiently so that these cells can actually start removing more than what gets deposited. It's a balance that needs to be reestablished. That is where we believe alternative pathway inhibitors have a problem because the classical pathway continues to feed C3 to these cells. And that is also why we believe that C5 is too far downstream because what we saw in PNH is that C5 inhibitors have no effect whatsoever on the deposition of C3 to cell surfaces. Next misconception, pegcetacoplan has no impact on visual acuity. It will take years to notice a difference. Why would people take this drug? So first of all, a very brief notion on visual acuity. Visual acuity is really foveal acuity. What does that mean? When you go to a retinal specialist like Dr. Wykoff or somebody else, you look at Snellen charts and you expect it to read the letters, which all of you have probably done to do that, all you need is the central portion of your vision, right? And if I give you just a pin prick, you may be able to read the chart. You may actually be able to read the small letters better than the big letters. But if I ask you to cross the street here in New York, that's very different. That's how you should think about the impact on function of this disease compared to what the visual acuity really represents. And quite frankly, that is why the FDA and most regulatory organizations do not consider visual acuity an actual or a clinically meaningful representation of the visual decline in this disease. Next misconception. How can we trust the FILLY data? Well, because what we did in FILLY is not just read out the primary endpoints. I mean we went about as wide and as deep as you could possibly go in a clinical trial. And without going into the details, they're well known to you or you can find them on our website and in our materials. It is quite extraordinary how every single analysis that we do univariate, multivariate, intrapatient, interpatients in the time frame, beyond the time frame within the zone of GA, outside of the zone of GA, all of that pointed in the same direction. Whilst all of this just random, it would be quite an extraordinary random events, but we believe that all of this points us in the right direction. And last but not least, FILLY had safety issues, pegcetacoplan causes wet AMD and had 2 cases of infectious endophthalmitis. I'm going to start with the infectious endophthalmitis. This is, unfortunately, a consequence or a side effect, I should say, of doing intravitreal injections. You will also find cases of infectious endophthalmitis when you inject anti-VEGF agents. You want that to be as low as possible. The barometer for us there is what is the precedent in other clinical trials that were done with anti-VEGFs and based on the fact that we had 1,500 or so injections in the Phase II clinical trial that is more or less on par with what you should expect based on the natural history. Then going to the wet AMD phenomenon. I want to start off by saying that, and this is really, really important throughout kind of all of the noise, the distinction is rarely made between choroidal neovascularization, which is the presence of new blood vessels in the retina, and exudation, which is these blood vessels actually leaking blood or exudate into the retina. And the reason why that matters, and quite frankly, even in the retinal field, right, I mean, we've made that mistake for a very long time, as we call it classical CNV, or we call it occult CNV, but with the old imaging techniques, we don't measure CNV. We actually measure exudation, looking at Charles, I don't say anything stupid here, right? That matters because as it turns out with the new imaging technologies that we have is you can have patients with what we occult CNV or type 1 membranes, which sit between the retina and the brooks membrane in patients with GA that are not leaky. So the membrane is a -- but the leakage is not there. And it turns out when you look retrospectively at FILLY that probably a lot of the patients that had exudates came from that particular category. And that then creates an interesting question around what is the biology that is going on there. But 2 important things led in the Phase II clinical trial to an imbalance between the group that we believe have led to kind of higher than you should expect numbers in the Phase II clinical trial. The first one is that in the Phase II clinical trial in FILLY, the readers were masked but the physicians knew who was actually getting a real injection and who was getting a sham, which is not a real injection, but just the tapping of the cornea. And, sorry -- the cornea of [indiscernible]. The -- so in the Phase II clinical trial, when there were small exudates that appeared in the retina, some physicians started overtreating that. The second important parameter to bear in mind is that in the Phase II clinical trial, we had a lot of patients, 38% of patients who started the study having already wet AMD in their contralateral eye, GA in the study, of course. But the contralateral eye already had wet AMD. And if you compare that 38% number to the normal demographic, that should be approximately 20%. So we had almost twice as many patients coming into the study, as you would expect based on the natural distribution. And that is rooted in the fact that during those days, we were competing with Genentech Roche on the enrollment of the studies. So to kind of understand how important that is or how much that matters that patients that start off with that particular phenotype have a threefold higher risk of developing exudates in the GA, either patient that has pure dry geographic atrophy. And to put that in numbers over the course of 2 years, patients coming from that category will develop within AMD in 22% of cases compared to 8% in patients that start off with a pure dry form of GA. Another question that we get quite regularly is, well, what is acceptable? What I can tell you right now, what is already acceptable is what we saw in FILLY, right? And that is reflected in the fact that in the Phase III clinical trial on that background information, the investigators who know that these exudates were mild in nature and other treat patients, right? And enrolled that study faster than any Phase III would have been enrolled had it not been for COVID. And that in itself is a phenotype that is acceptable. But it is reasonable to wait for the Phase III results and to expect a lower rate of exudation or on the fact that the demographics will be different and that the investigator bias will be controlled. All right. Then, of course, this is needless to say, an enormous problem with a current global prevalence of about 5 million patients, of which we believe between U.S. and Europe, about 845,000 patients would be candidates for real treatments. And I'm going to hand it over now to Dr. Wykoff, who is here with us. Charlie was an investigator in our clinical trials and has been an incredible support to us. Thank you so much for joining us.

Good. Awesome. Thank you. What a privileged to be here with all of you to talk about something near and dear to my heart and my clinical research interest, the unmet need of geographic atrophy, and I'll jump right in for respect of time. So you've seen these numbers on the left a bunch of times. You hear people talk about epidemiology of this a lot. And what's interesting to me is that I think these numbers are actually a gross underrepresentation of the burden of this disease, right? Because most of these epidemiologic studies have look mostly at patients with frank large areas of geographic atrophy without wet AMD. But if you include patients with small areas of GA, if you include the patients that Cedric beautifully alluded to with concurrent wet AMD with macular atrophy, and then if you include the patients with sort of this high-risk intermediate dry AMD just on the precipice before they develop GA, all of a sudden, these numbers are tremendous. And we, as retina specialists, see these patients on a daily basis. And there's a lot of them that are begging for something to treat this disease process that is absolutely blinding. Now look at the right side of the slide. This is obviously the macula. Let me remind you what we're looking at, the little black circle on the right is the optic nerve. This is the fundus autofluorescence image. And these dark zones in the middle that kind of look like little islands or continents, this is where the turn geographic atrophy came from because it looks like a map. But I'm going to play a video now, and this is sequential fundus autofluorescence images over the course of about 4 years in the 75 to 80-year-old patient. And you can see these zones of so dead out of retina coalescent, And you can sort of believe here that you would lose most of your good central vision. Remember, the macula is about the surface area of a nickel and it accounts for maybe 90% of your useful vision. So if you put that big black spot, right in the middle of your central vision, that's what these patients experience. And many, many prospective and retrospective analyses have tried to quantify what impact on patients' life, what does that impact on their vision. What we've seen repeatedly is though, even though historically, people have referred to this as sort of the slowly progressive form of AMD, those terms were always misleading. These patients, on average, lose about a line of vision per year. Again, this is inexorable, progressive, irreversible no treatment process. And in this analysis, by Usha, a beautiful piece of work out of the U.K. published a couple of years ago, she saw a teen to 10 letters lost over the course of 2 years of follow-up, dramatic amount of vision loss. But as Cedric pointed out, the bullet points on the left of this slide are much more difficult to quantify. But if you talk to patients with GA and you actually listen to what they say, they talk about a lot more than just their central ability to read letters and numbers. They talk about contrast sensitivity, about inability to adapt to dark settings about color vision changes and distortion, So it's more than just central vision for these patients. And that's why that broader population of patients with earlier stages of GA and even intermediate AMD becomes so important in this disease process. So in an attempt to try to sort of unpack what that means for a given patient, I had the privilege to interview this guy. Rob, this is a patient with geographic atrophy, who tried to describe what he experienced, and we're distilling a long interview into 3 minutes play the video. [Presentation]

When did you first realize that you had a problem with your vision?

About 8 years ago, might be going on now, but I was visiting my mom and Arizona, I corrected an eye open in the middle of the night to check the time. And one of the LCD things on a numeral without, which is, I've never seen that happen before. Now I'm curious. I opened my second eye to look at it and everything is just fine. I repeated that process again and said, it's not the clock, it's me. And as soon as I got home from that visit scheduled an appointment with my ophthalmologist.

Okay. So you go to see your ophthalmologist and what happened then?

Well, the first gentleman, I went to was he did all the tests took all the pictures said you have macular degeneration geographic atrophy, which is talking another language to me, I said, "what's that mean doc," and he says, "You're going to go blind.

That says a lot. So when that first person mentioned the word blindness to you, what did that mean? And what does blindness mean to you today?

Well, at the time of the total absolute blindness to me, I thought, At this point, I'd be looking at dark.

Yes.

And it was just horrible, absolutely horrible, just something to hear because my vision more than any other sense that I have was most important to me. And what it means today is I have -- first of all, I have blindness that any truly blind person would die for, but it's still really, really bad. I don't have any central vision to speak of, but yet I tell people kind of jokingly, I see pretty good unless I want to look at something.

So you mentioned that you started noticing this when you closed 1 eye about 8 years ago. how fast or slow has it progressed to the point where it is now?

To me, it's been very fast just because of the fact it's 8 years and, and I'm not driving, not reading, not doing tons of plays still love to do.

And so do you find that this visual impairment sort of limits your social outreach and your ability to connect with people and get out of the house?

Yes, it does. And the reason I hesitated before I answered that, but I can only get out of the house and do stuff on somebody else's time frame. Saturday morning, if I want to go to the club for breakfast, I have to rely on Jerry to pick me up. He's happy to do it, but I can't get in the car and do what I want to do. I know that sounds very selfish, but that's fact of the matter.

So Rob, really was eloquent. And I'd be happy to go into more details of what he said and what these patients experience. It's very real for these patients and their community. Let's pivot now and go into a discussion of the FILLY data that Cedric beautifully summarized and of course is published. As you will recall, this was a single mass, randomized trial, it's 246 patients with geographic as you randomized equally to pegcetacoplan 15 milligrams monthly or every other month versus sham, and the sham patients were split equally into monthly versus every other month sham injections. Of course, the primary endpoint was change in geographic atrophy lesion area from baseline to 112. And the elegant design of this trial was really nice to be able to see a biological effect because you had an on-treatment period followed by an off-treatment period during months 12 to 18. You know the results of that. And then this, of course, is the primary endpoint data. And the key point that you've heard now for a while is that the primary endpoint was clearly met in both the monthly dose patients and the every other month those patients and 29% reduction in the every other month and monthly dose patients, respectively. But a key of any geographic atrophy trial, I'll always keep in mind, and this is where the devil is in the details is to make sure you look at the control arm. What is the control arm are you using FILLY eye? Are you using sham control here, obviously, but what's the growth rate of that population? And here, we see the growth rate is 0.35 millimeters. Remember on the y-axis. We're looking at the square root transformation, which kind of normalizes for baseline lesion size. And then at the bottom of this slide, we're comparing that growth rate of the sham population to the largest Phase III program by far in this space so far, which was the chrome inspectory data set nearly 600 patients with sham treatment showing an almost identical growth rate, suggesting that this growth rate in FILLY is very consistent with what you would expect from natural history, suggesting that the effect here of the drug appears to be real. But then, of course, you can play with these numbers in many different ways. And it turns out on the left here, this is the square transformation I just showed you on the previous slide. And on the right is the absolute or untransformed lesion size, It doesn't matter how you play with these numbers. The effect appears to be the same with a 20% to 30% reduction in growth of geographic atrophy at that 1-year time point with pegcetacoplan every other month and every month, respectively. From a safety perspective, sort of the key observation that Cedric referred to was this observation of exudative AMD diagnosis from an investigator determined perspective. This was fascinating. It was unexpected, at least from my perspective. It's amazing how this has rippled through and affected the entire retina community, trying to, there's something here, I believe, that speaking to us about the biology of AMD and the biology of complement in the eye and the biology of inhibition of the complement cascade, there's still so much to learn here. But as you know, at 1 year, 16% versus 6% of the monthly and every other month dose patients developed exudative of AMD again, investigator term versus 1% of sham. Of interest, all of these cases were occult meaning that they were probably underneath the RPE, the more slow-growing variant. There appeared to be no meaningful impact on vision, which was very important. We recently published this data comprehensively, it's online in the Journal Ophthalmology, And then during the Phase II trial, the patients discontinued treatment with pegcetacoplan, and most were treated with anti-VEGF injections and the majority of these had a robust response as you would expect. Otherwise, the safety, this program appeared in line with other studies of intra administered agents. And then serious adverse events are obviously reported and important to consider. So in a few slides Jeff will then go through sort of the Phase III trial, where that is anticipated time lines, an incredibly important data set for the entire retina and ophthalmic community. But if we broaden the perspective for a second, and I tend to be a hopeful and positive guy in this space, and I think that in the near future, we are going to have something to treat patients that slow the progression of geographic atrophy. But what if you could take something and actually prevent the development of geographic atrophy or at least slow the development? So not just treat wet AMD, shown here on the left, and slow the progression of GA, but what if you could take a step back and go earlier in this disease process and actually hit it earlier before these patients develop GA. That would be sort of the next horizon, right, after we have a medicine that can slow the progression. And the data I'm going to show you, and that's been put forward by [indiscernible], really an elegant collection of data suggests that maybe pegcetacoplan can play that role. But before I review that data, we've got to take a step deep into the weeds here because we talk about geographic atrophy, but what does that mean? These analyses are really only possible once you can get very specific and define what GA is at an anatomic level and what the precursor lesions look like. So GA, the new term for GA is essentially cRORA. You haven't heard that term, you're going to hear a lot about it, I recommend you read about it, there's a group called the CAM group that has defined these terms, a great group of sort of international collaborators cRORA stands for complete RPE and outer retinal atrophy, and it's sort of a clear anatomic OCT-based definition of what geographic atrophy is. So the next question is, okay, that's GA, what comes before GA? Well, this is the lesion iRORA that is essentially immediately perceived geographic atrophy. So right on the edge of what GA will become. And there are now multiple natural history studies retrospectively, that are defining this rate of progression of iRORA lesions into cRORA lesions, essentially the development or the genesis of geographic atrophy. This is, we've needed this in the field for a long time, and we finally, have it. So with these definitions, and there's a lot more complexity around these terms that I'm glossing over here and other terms that are related. It's worth looking them up. But if you look in the FILLY data, so we went back and we looked at all of the iRORA lesions that could be identified in the eyes within the FILLY Phase II trial, of course, post-hoc analysis here, this isn't, the ability to define these lesions didn't exist when FILLY started. So when you look at these lesions on OCT, you find all the iRORA lesions and then you look at the rate of progression from iRORA to cRORA. Or in other words, the development of new areas of geographic atrophy over the course of the 1 year of active treatment in FILLY. And what you saw on the gray bars here is that 82% of the or lesions, if you will, and this was done at the patient level as well as the lesion level, 82% progressed to new areas of GA outside of the areas of GA at baseline in the sham-treated patients. Whereas with pegcetacoplan treatment, we saw a significant, and I would say, clinically meaningful reduction in the development of these new lesions of geographic atrophy, down to 50% to 58%. Quite exciting data suggesting that maybe this drug really could work, not just slow the progression of GA once you have it, but to slow the development in the first place. So key takeaways from this segment. Obviously, GA has a huge unmet need. You've been hearing that for decades, hopefully at this point. But it is much larger than the simple epidemiologic numbers would point us to, I would tell you. And the question comes up all the time, our patients are really going to take this drug right a specialist office are overflowing with patients that would love something to slow the progression of this disease. Clearly, pegcetacoplan met the primary endpoint in FILLY was slowing of GA growth in a dose-dependent fashion. And maybe most interestingly to me today is this possibility that pegcetacoplan could be moved earlier in the disease process to stop this before it begins. So with that, I'd be happy to take questions during the Q&A, and I'll pass it over to Jeff Eisele.

Great. Thank you, Dr. Wykoff.

Thanks, Jeff.

Good. So my name is Jeff Eisele, and I am the program lead for the ophthalmology programs of Apellis. And it's my pleasure excitement here today to talk about what's next for pegcetacoplan in ophthalmology and what's coming up in the next few months. But first, I just want to say something about our regular engagement with key stakeholders including retina specialists, general ophthalmologist, patient advocacy groups and others, and what we hear from them, their perspectives on the treatment of GA and the need for a treatment for GA. So generally, we learned that there's a great anticipation for pegcetacoplan, and that retina specialists are extremely enthusiastic but the prospect of having the first ever treatment for GA patients for their patients. Our recent market research, review unmet medical need is well recognized and 94% of the retina specialists that we surveyed believe that GA poses a significant burden to the quality of life of their patients, and 84% believe that slowing lesion growth is the most important goal in preserving vision for their patients. And in fact, most of the retina specialists mentioned that they would immediately notify their patients if a new treatment for GA became available. When we presented to the retina specialists our target product profile for geographic atrophy for pegcetacoplan in GA, you can see here on the right side some of their feedback, some of their thoughts, the quotes by those participants confirming our approach with C3, the quality of our study designs and what would constitute a meaningful outcome for our studies. Next slide. So now it's my pleasure to provide an overview of the DERBY and OAKS Phase III studies. In DERBY and OAKS, we have 2 large, well-controlled Phase III studies to compare pegcetacoplan monthly and every other month intravitreal injections with sham injections. The primary endpoint is changed from baseline in the total area of GA lesion, and it will be assessed at month 12. The study continues for a total of 24 months and patients who remained randomized for the duration of the study. The studies enroll a total of 1,258 patients, and this was done in 15 months in spite of the challenges to the global COVID-19 pandemic. This speaks to the recognition of the need and the patient desire to have treatment. So DERBY and OAKS, and I think this is important, include a broad GA patient population that's reflective of the real-world GA patients and consistent with the FILLY trial population, and the study design is consistent with the FILLY trial. There are just a couple of points I want to make about the study design today. The first is the DERBY and OAKS studied 2 pathologies, And this is important. And most important of those pathologies is the monthly treatment arm, which provides an assessment of the maximum efficacy potential of pegcetacoplan. The second pathology is the every other month arm, and this provides an assessment of the potential for more convenient dosing regimens for patients and supports understanding if there are patients who could be adequately treatment with a less frequent dosing regimen. And secondly, DERBY and OAKS allow patients with fellow eye CNV in both foveal and extrafoveal lesions. As mentioned, the primary efficacy endpoint is changed from baseline in the total area of GA lesion and the primary readout will be at month 12. The study continues, as I said, for a total of 24 months. And we've also included additional visual function and quality of life endpoints in DERBY and OAKS that were not included in FILLY. Secondary functional endpoints will be assessed at month 12 but formally tested only at month 24, and lesion growth will be assessed not only for the primary endpoint of month 12 but also at month 24 as well. We continue to believe that both studies are well powered for the primary endpoint. On the monthly arm, we expect minimal impact from COVID-19 and missed injections, missed visits due to COVID-19. And I want to reiterate that the monthly arm is our top priority, and we believe that we only need a positive result in the monthly arm for regulatory filing and approval. On the every other month arm, where 1 missed visit could result in a 4-month interval without treatment, the potential impact of COVID-19 is obviously greater. That said, we still remain confident in a positive result for every other month. We've always considered this a bonus on top of the monthly arm. And as noted earlier, every other month provides an assessment of the potential for a more convenient dosing regimen. We believe to get regulatory approval and to bring the first product to market for the treatment of GA month of the target. It is most important to understand and demonstrate the potential of pegcetacoplan in GA. Just briefly on the statistics and the modeling. So similar to FILLY will fit a mixed model with repeated measures for the primary analysis. Basically, the same model will be fit, but we will conduct additional supportive analyses to demonstrate and assess the robustness of the results and then that account for the potential impact of missed visits and injections, especially or specifically those due to COVID-19. As has already been mentioned, the top line results from DERBY and OAKS are expected in September. We will present the primary endpoint for both the monthly and every other month arms, treatment arms and the safety profile, which will include an overall summary of safety and specifically rates of exudations and intraocular inflammation. And now I'd just like to briefly touch on intermediate AMD and our plans there. So targeting intermediate AMD represents a significant opportunity to delay or prevent progression to advanced forms of AMD. As we saw in Dr. Wykoff's presentation, a post-hoc analysis from FILLY so the potential of pegcetacoplan for the treatment of intermediate patients. Following a positive GA readout, and we plan to rapidly advance the pegcetacoplan program in intermediate AMD, and preparation for this is already underway. And we expect to initiate a pivotal study in the first half of next year following feedback from regulators on the study design and the regulatory pathway. So thank you, and I turn it over to my colleague again, Lukas Scheibler.

Thank you, Jeff. So we want to talk about what is coming next after pegcetacoplan and how we will enter wet AMD with APL-2006. If you look at the landscape of AMD, we have intermediate AMD in the United States. We believe with what Jeff just presented to you with pegcetacoplan, we may have maybe 1.3 million patients who are at risk who can be treated with pegcetacoplan. Of course, in the middle here is advanced AMD with geographic atrophy, about 4 million people in the United States who are eligible, if successful, for treatment with pegcetacoplan. And then there are another 6 million people who suffer from wet AMD. But importantly, there is a good proportion of these patients who have both forms of advanced AMD, both geographic atrophy as well as wet AMD. We would like to make a therapy for those, but also for all the other wet AMD patients. Because if you look at the outcome of wet AMD therapies. And here on the left side, you see results from the [indiscernible] study, where patients were treated over a course of time with AMD therapies like Eylea or Lucentis. And they looked at how many patients developed a geographic atrophy in the course of the therapy. And you can see about 30% of the patients developed geographic atrophy over a period of 2 years when they were treated with anti-VGF therapy for their wet AMD for their CNV condition. In addition, there are reports in the literature in the middle, which link the treatment of wet AMD with anti-VEGF therapy to an increase in levels of free, And most importantly, maybe from the CAT study. If you look at the treatment outcome in patients treated with anti-VEGF for their CNV is that the treatment outcome is really different between patients who develop geographic atrophy or macular atrophy and patients who do not develop it. In this study at about 5 years down the road is a numerical difference of about 10 letters or more even, which is observed after 5 years of treatment. And we thought this is an opportunity for us to enter the wet AMD market if we can also prevent geographic atrophy. And we've defined for our molecule the following target profile. First of all, want to produce non-inferior best-corrected visual acuity outcome as Eylea or Lucentis for that matter, at the 1-year time point. So in a short period of time, we want to have the same benefit as these drugs do to patients with wet AMD. In addition to this, we want to reduce the growth or reduce the onset of geographic atrophy in these patients, and that will translate to a superior functional outcome over a longer term of therapy. We want to treat the patients every 3 months or less frequent even. And of course, we need similar safety as these established therapies I mentioned above. To achieve this, we created a new molecule, which is shown here on a schematic view, the anti-VEGF part of this is coming from ranibizumab, and we attached to the C-terminal handle of this molecule, 2 moieties. First of all, protein sequence, which allows us to control the half-life of the molecule in the vitreous cavity. And we have shown that we can increase with this sequence, the half-life by twofold in a nonhuman primate. And last but not least, we are attached at the very bottom of it, APL-1030, a molecule which Dave Eyerman has already introduced for the treatment of CNS diseases. And this molecule provides us with the C3/C3b inhibition problems. Together, we think this molecule has the potential to provide a superior treatment outcome for patients with wet AMD. It may allow less frequent dosing, Eylea Lucentis, and we are well on track to file an IND next year. I will just share with you 2 data points of this molecule. On the left, we compare the ability of this new molecule APL-2006 in inhibiting the complement cascade, in this case, the classical pathway versus pegcetacoplan. And you can see the 2 molecules behave fairly similar, with APL-2006 being numerically slightly better. On the right, we compare the VEGF inhibitory potential versus Lucentis of this molecule, and they are pretty much indistinguishable and the same. It is the so-called HUVEC assay. So with this, this is the molecule we bring into the clinic next year for the treatment of wet AMD. And the third leg of our stool as how we move forward is to push this into gene therapy. Dave Eyerman has already talked to you about gene therapies and how we will use gene therapies to secrete APL-1030 in the brain for the treatment of CNS diseases. We can use similar constructs as this construct is using for CNS diseases for the eye, and we can show that we can secrete in vitro at least, here on the left, that we can secrete the molecule in vitro. And we are in the midst of rabbit and monkey studies to demonstrate that this can also be done in vivo in ocular tissues. So with this -- I was asked to speed up, so I'm going a little bit faster. With this, I want to summarize where we are going to go and what we're going to do. Of course, the most important readout is coming in September with the pegcetacoplan Phase III study readout in geographic atrophy. We are then planning to use pegcetacoplan to expand the indication from geographic atrophy to intermediate AMD as well. And then next year, we start the development of APL-2006 for the treatment of wet AMD, where we think we will have a superior product over what is currently on the market. And last but not least, we will exploit our gene therapy platform to create therapies both for intermediate AMD as well for advanced AMD. And with this, I would like to start the Q&A session. Get some chairs, guys.

Charlie, yes? All right. Wonderful. So we're going to have -- you're only allowed to use the house chairs. Right. It's a full stage. Do you want to take this away? All right. Thank you so much. Jeff, over to you.

Okay. I'd like to also announce that we have Dr. Nancy Holekamp online as a virtual participant in the Q&A today. She's a retina specialist based in St. Louis. And I thought I would just start the Q&A with a question to Cedric first before we get to audience questions. We've got a big event coming up. It's been years in the making, but there were some challenges at the beginning of the program. Not always the best memories to bring back for you, but maybe you can talk a little bit about what happened and how you and the Apellis team are working together with key members of the retina community actually solve those problems.

Thank you, Jeff. That's not a planted question by any means. We wanted -- I wanted to kind of go back to what happened at the beginning of the Phase III clinical trial. For those of you that may remember that, we started our Phase III in September of 2018. And we randomized, I should say, 6 subjects, and 4 of the 6 subjects in a 2:1 randomization developed inflammation. And as you know, in retrospect now, what we know happened was that an impurity in the scale-up of the manufacturing has found its way into the product that ultimately required a redo of the manufacturing process. That issue was completely resolved. But I wanted to bring it up because Charlie here with us today. And Dr. Wykoff at the time was part of what I think was kind of an unbelievable effort where we were so fortunate and privileged to see, and Nancy as well, I mean, to work on trying to resolve this in collaboration. And to put this in perspective, at the American Academy of Ophthalmology, which, if I remember right, was [indiscernible].

Yes.

Yes. We had a Steering Committee meeting. And after doing some initial tox work, we were convinced that we had solved the issue and ready to restart the Phase III clinical trial, super excited and super happy. And then we had our Steering Committee meeting. And the retinal doctors told us, "Look, you cannot mess this up. If your Phase III shows this again when you start it, it's over. Let us do a Phase Ib study and see if this is really resolved or not." And at the time, you guys came to me and you said like, "Cedric, we're going to do this in record time." Between that meeting and the first patient dosed in that Phase Ib, 2 weeks passed, 2 weeks. For those of you that run clinical trials, you will appreciate that, that doesn't happen very often. And when those patients were dosed, after a couple of patients, it was better, but there was inflammation again. And where we thought it was a lot-specific problem, that told us that it was not a lot-specific problem but really something on the manufacturing. And one of -- it was a shameful moment for me because I had to call Charlie at the time and the other -- his colleagues, I mean, having essentially giving them a new product that was causing the same issue. I mean I was literally almost in tears when I had to call Charlie at the time. And he told me, he said, "Look, this is why we do this. Go and figure it out. And when you do, we'll try it again." And thank you, Charlie. And thank you, Nancy. I mean it was incredibly meaningful to us. We figured it out in about a month's time, reran the tox over Christmas; and end of January, reran the Phase Ib. And in the beginning of March, we started our Phase III clinical trial. So I just wanted to bring this up because, honestly, the retinal community, exemplified here by Nancy and Charlie, is just amazing, and that was great.

Yes. No, what a memory there. I mean we're so fortunate in the retina space to have a lot of fantastic innovation and collaboration between physicians and the industry side. That was a rare example of incredible levels of collaboration and chiefly, a company that was willing to be open to the possibilities of challenges and willing to adapt really, really quickly. I've never seen a program move that quickly from both the physician, the patient and the industry side. And fortunately, we got through it. I think everyone saw the unmet need. They believe in the science, and yet we put patients first cumulatively and fortunately got through it for the betterment of all.

Thank you. So I just wanted to make a brief note of that. And with that, okay, let's open it up to questions.

We'll take one from the audience.

It's Tazeen again from Bank of America. A couple of questions from me. I think in your prepared remarks, it might have been Jeff who said that based on your company's belief that for DERBY and OAKS, that hitting the primary endpoint just on the monthly arm will be sufficient for approval. Is that something that FDA has specifically said that you don't need to be statistically significant, let's say, for the every-other-month dosing arm? Or is it something that would have to be discussed after the data comes in? That's the first question.

I want to take this one. So we haven't had specifically this discussion with the FDA, but the study is designed where the primary endpoint is lesion growth. And the 2 are tested separately, right, whether it's every other month or monthly. So if we hit monthly, we've hit the first primary endpoint. And that should be sufficient. And that's our measure of the maximum effect of the drug, right? And this is the target.

Yes, these are not co-primary endpoints, right?

And then as it relates to gene therapy, so as you embark on pursuing this modality, how confident are you in picking your plasmids and your vectors at this early stage, just looking at what other gene therapy companies have experienced especially as some of them in particular have seen unwanted complement activation as a side effect. So as a company that focuses on complement, how are you going to approach that differently?

Well, in 2 fronts. First of all, we have -- so in order to -- we're very well aware that other companies have reported untoward effect which may be related to complement. And then we are -- our research is looking into these aspects of how our complement inhibitors can actually enable gene therapies in general. The second question is how are we selecting the plasmid -- the capsids was the question, correct? We are currently using both AAVs as well as lipid nanoparticles for delivery methods.

Phil Nadeau from Cowen. A few questions from us. First, for Dr. Wykoff. Just to get your thoughts on what is the minimally clinically meaningful difference on the primary endpoint, so how low can the reduction in lesion growth go for -- to still be impactful for patients in something that you prescribe?

Yes, it's an important question, and there's not a simple answer to that. And the reason I say that, from my perspective, when you look at the data cumulatively and you think about the duration that these patients are alive and the duration of this disease, it's a long-term disease. And we're so far still looking at the early stages of treatment. So what I'm most interested in is not what's the difference in growth rate at 6 months or 12 months but 18 months, 2 years, 3 years, 4 years, can you continue to shift the slope of that curve with continued C3 inhibition. To me, that's what gets really exciting because if we see 20%, 30%, to me, those are all in the same ballpark. Anything really over 15%, I think even lower, if it's statistically significant and then over longer periods of time continues to grow, that's what's meaningful. I want to see a biological signal. We've currently got nothing. So anything that is statistically significant, I would think would be meaningful as long as, over time, that continued to grow especially if that number were small.

That's helpful. And then a 2-part question: first part, for the company; second, back to you. On the endophthalmitis, Cedric, in the past, you've suggested that the cases of infection in Phase II could have been due to the formulation and the fact it had to be reconstituted. You didn't mention that today, so has your understanding of the possible cause of that endophthalmitis changed? And Dr. Wykoff, again to you, the company said 1 in 750 rate of endophthalmitis is in line with historical precedent for anti-VEGFs and whatnot. I was under the impression it was more like 1 in 5,000 endophthalmitis with anti-VEGF injections. Can you -- where do you think that number lies?

So there's a difference between clinical trials and in the real world, right? So first off, for reasons that we think we understand, in clinical trials, you will typically find a higher rate. And that's usually because physicians are -- get used to the product they're working with, right? Probably very, very small differences in how you inject it or what you do it on a 1,000-patient basis or 1,000-injection basis could kind of shift that balance potentially. So when you look at the trials with anti-VEGFs, it is actually very much in line with what historically has been associated there. As it relates to the Phase II to Phase III change, so in the Phase II clinical trial, we had a lyophilized product that was required to be reconstituted before the injection, and that was about -- not a 1-hour procedure but about 1 hour of letting it mix up properly on a shelf. And again, that's different from the routine that retinal specialists get to with an anti-VEGF where it's a prefilled syringe, it does what it need to do. So in the Phase III clinical trial, that lyophilized product is not lyophilized but actually a liquid preparation. So that whole kind of hour of dissolution of the product is gone, which may make a difference. But I want to point out one important thing here, and that is the notion that somehow complement sits in the vitreous and protects patients against endophthalmitis is fallacious, right? I mean the vitreous you should think of as a petri dish, right? I mean -- and if you happen to introduce a pathogen -- an external pathogen into the vitreous, probably even only one bacterium, it will grow, right? I mean, so the fact that a complement inhibiting agent would [ interfere ] with a naturally protective process in the vitreous is not correct. So we feel very good with where we stand, and we think that in Phase III, that will be confirmed. I don't know if you want to add to that?

Yes. No, certainly, from a -- if I think of that broadly, certainly, we, as clinicians in any company innovating in this space, we don't want to cause bad things, right? We don't want to cause endophthalmitis. It certainly is something that everyone looks at, and then everyone wants to certainly learn more in the Phase III, certainly. But to me, those numbers do not appear to be an outlier. They seem to be very consistent with numbers from other programs. You're dealing with a rare event. And it's critical to remember that even these huge Phase III trials are not powered to see differences between rare events and the safety events like endophthalmitis. So I think it's the challenge with small numbers, and those numbers don't look clinically meaningful to me.

Great. And last question from us is just on APL-2006. We're just curious why you're using ranibizumab instead of an Eylea-based construct in light of the share that Eylea's taking.

Lukas?

It's a purely technical choice of what drove us to use ranibizumab versus other VEGF inhibitors. And at the end of the day, what all we have in hand, this was a validated molecule and allowed us to move forward without taking additional risk due to an introduction of unknown entities.

Before I take the next question, I'd like to give Dr. Holekamp a chance to comment on the endophthalmitis or any of the other topics so far.

Well, thank you. Happy to be here. And I'll just echo what Dr. Wykoff was saying. When we look at the results, there's no signal here from my point of view that endophthalmitis rates are unusual compared to other clinical trials. And it's important to emphasize that there are rare events and difficult to study even in our largest Phase III clinical trials. It really takes a real-world experience, and clinical trials are just not that. So from what I've seen so far, I have no concerns about endophthalmitis with this clinical trial.

It's Alethia at Cantor. A couple of questions for you. One, with the secondary endpoints, like the microperimetry and different things like that, in light of how kind of complicated this disease is, like what are you guys kind of going to be looking at? And what do you think will compel maybe perhaps more skeptical physicians about just a sheer reduction in lesions? And then we've gotten some feedback that not all exudations are created equal. So I just want you to kind of talk about like maybe people aren't as well as they were and then the implications of just like maybe they need an injection every 6 months. And is that really the end of the world if they're seeing potential sustained reduction in lesion size? And then the last question is for the presenter who gave the great -- the video, the fireside chat. If that patient had seen the 29% reduction or so at the time point, like what would that mean for them in real life?

Do you want to take all of those, Charlie?

Sure. Sure, I'll jump right in. There's a lot that you touched on there, and I'll go to Rob maybe first, the patient that you brought up. It's hard to say on a given patient who's already lost so much vision. So this gentleman has -- I've never actually seen his anatomy. I don't know what his retina looks like. But it sounds like he's lost maybe 70% of his macular function. And so even in patients like that, I think that there is a potential role for medications to slow the progression of this disease because they're continuing to lose retina that is valuable territory. And eccentric fixation is very real in these patients of a geographic atrophy. Even once they've eclipsed their fovea and they no longer have foveal function, they still are using some part of their macular tissue for their preferred visual focus, a locus for vision. And so to preserve as much tissue as possible is critical. And so I think patients like him could benefit from this. There's no doubt. And then your previous question was related to...

It was the one about, sorry, exudation.

Yes.

And then also the one about the secondary endpoints.

Yes, critical. So not all exudations are created equal, I think, is a fascinating point. And again, broad picture here, we use clinicians and innovators who don't want to do things that harm patients. Certainly, wet macular degeneration that is untreated, the natural history for that is unforgiving and causes a lot of blindness. And so the concept that you might be inducing wet AMD here that then goes untreated is not what we're talking about, right? These patients were followed extremely carefully in this study. And at any sign of exudation, I think some of these patients may not have truly had true macular neovascularization. They may have just had a little bit of exudative change that was untreated because we are being sort of very aware of any possible conversion to the exudative form of AMD and then jumping on treating that because we as clinicians know that, that causes vision loss without treatment. That's why I think it's so important in the Phase III trial that it's been structured in a way to allow patients to continue to get pegcetacoplan as well as on-label anti-VEGF dosing and also to really make sure that there's a diagnosis, a firm diagnosis of a neovascular process before anti-VEGF therapy is initiated.

Nancy, would you like to add something to that?

Sure. Actually, I'd like to add a little bit about the first point that Charlie touched upon is the benefit to patients. I just -- you might tell I'm in the office today. I took a break to join you, and I saw a patient who's been in the clinical trial for wet AMD treatment with me for many years, 5, 6 years. She still has good central visual acuity. She sat down in the chair today, and she said, "You know, Dr. Holekamp, I'm losing peripheral vision. I can pick letters out from the eye chart, but I can tell that my vision is getting worse." And of course, she has that geographic atrophy pattern that's encroaching upon the fovea becoming closer and closer. So I think that with this unmet need, we're all looking for on any kind of progress or slowing of the progression of disease. And I think the value to each patient may be a little bit different depending on where their stage of disease is. But of course, this is the disease for the long haul, 2 years, 3 years, 4 years, 5 years. So the second thing I'd like to comment on is the secondary endpoints such as perimetry. Difficult to do, could be really compelling, it's why we include these endpoints in Phase III clinical trials and really looking forward to seeing the data from DERBY and OAKS.

Thank you so much, Nancy.

Madhu Kumar from Goldman Sachs. I'll start with the neurology question. So thinking about the neurology programs, the intrathecal administration programs, what is the PD biomarker in Phase I that will convince you that you're getting C3 pathway inhibition in the CNS to kind of bolster going into all these neurological indications?

Target engagement biomarker will be C3a and the CSF fluid. Beyond that, depending upon the disease state, we'll look for other disease-relevant fluid biomarkers in that compartment.

What gives you confidence that, that will get you the kind of prediction on pathway inhibition that kind of will predict activity on neurological...

Yes. So that will be used in conjunction actually with a radiotracer that we're developing, that we're actually going to use a zirconium-89 conjugate of APL-1030 to do a PET imaging study, to also look for biodistribution within the brain parenchyma itself. So the 2 things we believe will guide us to does drug get in the brain and is there enough of a PD effect to move forward.

Okay. And then 2 ophthalmology questions for Dr. Holekamp and Dr. Wykoff. So first one, related to something that Cedric mentioned at the beginning of the discussion on ophthalmology, his observation of difference in patient composition in FILLY versus other larger-scale GA trials, kind of explaining some of the difference in exudation rates on pegcetacoplan versus other drugs in the space. But also this notion that there's a biological thing going on where complement inhibition interplays with VEGF in some interesting ways. So to your understanding, like what -- if you were to split those 2 kind of outcomes, things about patient composition versus complement/VEGF biology, how much does each contribute to the observed CNV rates that we're seeing in FILLY? And then second question on kind of related to APL-2006, a kind of naive question for the -- really, for the company and for the physicians. What is a reason to give that drug versus pegcetacoplan or Lucentis?

Yes. I'll jump in with the exudation question. Just to sort of context set again, at the beginning of the FILLY trial, I certainly never heard anyone even hypothesized that we might see increased exudation. It just wasn't on the table as far as I was aware from a biology perspective. And so we were learning as we went. And so sort of the choice was made essentially on the fly to stop treating these patients from an investigator and a sponsor perspective with pegcetacoplan and then treat them with anti-VEGF therapy. That's what we thought these patients needed. Looking back, we wish we'd done things differently, we'd standardized imaging and wish we had continued the study medication in the Phase II trial. Unfortunately, both of those things have been modified into the Phase III. And the questions you asked are why we actually went back at a very detailed level and just recently reported under peer review all of the data that we have around those patients. I encourage you guys to read that paper because very transparent that we put everything out there, and it's an incomplete story. I mean a lot of back and forth actually with the journal and the reviewers because it's not a watertight story. There's no clear answer to your question. But my own personal bias here is that it's multifactorial. Part of it is due to patient composition of the FILLY Phase II trial. We were competing with enrollment during the lampalizumab enrollment, so that excluded fellow eye wet AMD. So those patients naturally got funneled into FILLY. So we had a higher yet enrichment of that patient population. And in that vein, we have a lot of data from [ ARIS ], from Sunness, from Usha Chakravarthy's work, many papers showing that if you have a history of fellow eye wet, you have a much greater chance of conversion to exudative AMD in the GA eye, in the study eye. So we know that, that rate is different among that patient population. So that explains part of it. But I do think there's something going on here from a biology perspective when you're inhibiting C3 and maybe other molecules in the pathway that you change the local dynamic. Maybe that's explained by changing the phenotype of macrophages from an M1 to an M2 phenotype, where they become less macrophage phagocytic-based and more pro-angiogenic-based, and therefore, you have a little bit of exudation. Or these quiescent macular neovascular membranes that are type 1 begin to leak, so maybe we're seeing some conversion of those, which can partially explain it. And then I think the third thing that can explain it is the concept that it was single masked. And if patients are losing vision in the trial and you're seeing a little bit of cystic changes, which you can see in GA that's not related to exudation, maybe sometime the trigger was pulled a little sooner than it needed to be to start anti-VEGF therapy because, again, the last thing any physician wants to do is allow a neovascular complex to grow with exudation because we know that causes vision loss.

On to your 2006 question, for us, when we look at the geographic atrophy or advanced AMD, advanced AMD, the base treatment for advanced AMD is pegcetacoplan. It's an atrophic disease. And in some patients, these patients also develop CNV on top of the atrophy. But there is advanced AMD. The treatment is pegcetacoplan, the C3 inhibitor. And if you have, in addition to that, also wet AMD or CNV on top of it, then 2006 can be a choice. But there will be patients who will have no CNV developed in the course of the therapy. Some will and -- I mean these are speculations, and they're all good, I think, that they're reasonable of why this may happen. But we don't know exactly what pushes it to with CNV. But if you do get CNV, then, well, we develop this with the hypothesis in mind that this will be a superior outcome for patients who are treated for the CNV if you treat both forms, GA and CNV.

Nancy, anything you'd like to add?

Yes. So my connection is a little unstable, but what I'll add is that because there was a broader GA population, we have a broader genetic profile of every single patient. And if you're asking about biology, biology is determined by genetics. And when I see an unexpected adverse event like perhaps an increased rate of CNV. I see it as an opportunity to better understand the genetics, the wide variety of genetics of patients with geographic atrophy or advanced forms of AMD. We don't understand it completely yet, but if we're smart, we'll take a look at these clinical trial results, and we'll use them to figure out who's at risk because Charlie and I both know there are some people who never ever get choroidal neovascularization. And they probably have a different genetic makeup. We just haven't fully figured it out yet.

Okay. Next question, yes, please?

It's Ellie Merle from UBS again. Just in terms of the undiagnosed patients with GA, can you help us understand a little bit of sort of where these patients are in terms of the types of physicians, whether there are some that are still in the general ophthalmologist practice that haven't made it to retinal specialists yet, just in terms of understanding the overall opportunity if there is a treatment approved? And then just a logistics question in terms of the statistics. Can you just remind us if there were any changes in terms of the mix effect model in terms of either the variables or the weighting across the variables that you're using between Phase II and Phase III? And then also just from a statistics perspective, was the discussion with the FDA around sort of showing stats safe around the pooled studies? Or what would be sort of the plan if 1 of the 2 were stats safe and the other was not say on the monthly arm?

So I can quickly take the 2 stats questions, and then maybe, Nancy, you can address the first question. The only change to the model from FILLY is the addition of a factor for a fellow eye CNV. Otherwise, it's the same model. And then your question was around if one study is positive and other not versus a pooled analysis. So for the primary endpoint, we're not doing -- we will do pooled data, but the analyses are done based on the individual studies, right? So no discussion with FDA on what would happen if one were positive and one were negative.

So I can address the where are all the GA patients. And we surveyed the IRIS Registry database, which is about 69,000 eyes. And the IRIS Registry is through the American Academy of Ophthalmology. And we learned something very interesting that retina specialists are not seeing the majority of these patients. And if they're not being seen by a retina specialist, they are less likely to follow up. So if they're seeing an ophthalmologist or an optometrist, they're not coming back, and that's because of the perceived notion -- well, it's a true notion that there is no treatment. So that's kind of what we've learned by looking at a very, very broad survey of what's going on in eye doctors' practices across the United States is that they -- the patients that are out there, they're not necessarily with the retina specialists. But if they are with the retina specialists, they are coming back more often on a consistent basis, to be followed. And so I think there's work to be done there to get the majority of patients to retina specialists.

Thank you. So we can take one last question, please.

Justin Kim from Oppenheimer. Just thinking about sort of the maturity of the landscape in wet AMD and how the focus has been on addressing treatment burden there. And Dr. Wykoff, you commented a little bit how you wanted to see effects at year 2, 3, 4, where it can be challenging to keep patients on consistent injections. Just wondering, do you see differences in the GA population that might be different in terms of the motivations to stay on therapy and be motivated to have consistent treatment?

Yes, it's a great question, right? The question sort of relates to where are the GA patients, is the next part of that, where are they going to go once we have treatments that are available. And they get 1 or 2 shots, they don't notice the difference, so they stop getting treatment versus are they going to be consistent. That's going to be very patient dependent, very patient specific. And we see that with wet AMD, right? We use wet AMD drugs all the time, lots and lots and lots of injections, and yet there's pretty good data that a lot of patients don't get the number of injections they should, and a lot of patients stopped getting treatment. And a lot of that's very patient specific. I mean Nancy and I and all retina specialists have clinics full of patients that are very consistent with their wet AMD treatment, and yet, of course, there are a lot of patients that fall off. That's going to be on the sort of shoulders of the patient and their support network and our communities in general to help them get the care that they need and they deserve. But I can say that if you look at the retention rates, for example, in geographic atrophy studies overall, they're remarkably good. These patients are remarkably consistent in GA studies compared to, for example, DME or DR studies. So I do think this is a patient population that -- especially with frank areas of GA, they know they have a problem. They sort of understand this concept, they're not going to be seeing better with the injections, and they want to preserve what they have. So I think there's a level of motivation here that I think is still underappreciated by sort of us as a community. These patients know they have a problem, and they want to get better, and they want anything that will get them there.

Can I just add on quickly to that, Charlie? I agree 100%. I just finished doing a survey in the wet AMD population about the motivators for compliance. And the #1 was patient-physician relationship and #2 was patient education. And so I think with the role of physicians educating patients, I think that it will certainly be a challenge, but I think it's doable if we focus on those 2 things.

Okay. Yes, thank you so much, Charlie and Nancy, for joining us here today. And that is the end of the ophthalmology session. So maybe we can give our -- all of our teams a grand round of applause.

So as we get to the last session here, so in the beginning of our R&D Day, we talked about how, 4 years ago, we set out to try to own complements. And the -- that distracted me. Last year, as we looked at everything that we were doing and that we presented to you today, we also realized that there was one piece missing in this whole equation. And it's kind of remarkable to think about in the current context, as you will see in a second, but that is, of course, gene editing. Gene editing in the context of complement biology is really interesting because, on one hand, you should remember that the first breakthrough out of the genome-wide association studies was in 2005 in the retina when the association was discovered between complements and patients with age-related macular degeneration. So kind of the heritage of the genetics in a complex biological system are probably stronger in complements than they are anywhere else. So what we decided to do was to reach out and look at the gene editing platforms that were out there. And we have one more thing for you today, and that is we wanted to announce that we are entering into a partnership with Beam Therapeutics. This is an exclusive research collaboration on everything related to complements, to apply base editing to discover novel therapies for complement-driven diseases. This is going to be a program that covers specifically 6 programs in 3 organs: in the liver, the eye and the brain, on which you have heard a lot today. We chose base editing for a couple of reasons, and we chose Beam for a couple of reasons. One is, of course, that with Beam's technology, we can do what is arguably the microsurgery of editing in the genome, which we believe that, again, in the context of complement is especially attractive. But over the last 9 months, as we kind of elaborated and really went deep into understanding what we are going to do together in this very broad collaboration, we came to appreciate kind of the enormous scientific prowess that Beam holds, their integrity and the cultural match that they have with us. I mean we've, quite frankly, become friends over the last 9 months. And we really look forward to kind of engaging in a program that I think not just as it relates to complement but as it relates to starting to think about taking a homeostatic system that is put out of control and trying to bring it back and apply gene editing to that rather than kind of what we're used to now the corrections on a [ DNA ] basis, that is going to be particularly exciting for us. And with that announcement, I want to bring here Pascal Deschatelets, our Chief Scientific Officer, to briefly elaborate on kind of what base editing with Beam is going to do for us. It will be top level, and we'll have a brief discussion with a Q&A after that. Pascal?

Thank you very much. So very simply, as Cedric says, we're excited to work with Beam. Gene editing is, I would say, getting a little bit more mature. There's great Intellia data that came out last week. So that kind of puts us at the stage. And to talk a little bit more about -- people are a bit more familiar with the basic conventional CRISPR approach, which is basically you cut both strands of the DNA. And when the cell repairs the damage, typically, they'll do it by actually messing up the gene, so you end up science-ing the gene, preventing the formation of the full protein. Well, base editing is kind of the next generation beyond that. While nuclease editing is more like an axe, base editing is more like a scalpel. So the idea is you'll come in, and you'll only change very specifically a single nuclear base in the gene of interest. So if you look at very high level in the technology, they both use a CRISPR complex, which will bring a -- with the use of a guide RNA, will bring the entire complex to the DNA the piece you want to edit, except the Beam technology actually adds a deaminase complex, which is an enzyme that will come in and will actually very specifically change one single nuclear base to make a very specific change. The CRISPR protein also has been edited, so instead of cleaving both DNA strands, we only cleave one DNA strand. So the cell, when it sees the mismatch, will correct the mismatch, favoring the mutation you want to introduce. And that ends up giving a very specific modification, much less under our genetic modification and disruption and something that hopefully is going to bring forward much superior therapies on the brain, for example, stop codon to expression for a specific protein or introduce a mutation you think is going to be beneficial to treat certain conditions. So we're very excited. 5 years, we're going to focus initially on C3, which we know very well. We know how to inhibit C3. We also understand how to science C3 and how we can deploy that to treat diseases. And then there's other targets we think are interesting in 3 different compartments: the liver, meaning systemic treatment; then the eye, which is important for all the ophthalmologic indication. We think, again, if you go in the eye, you can do multiple diseases. And then the CNS, the brain, which we think is holy grail if you're thinking about impact in the long term. So that's it. Cedric and Lukas?

Thank you, Pascal. Thank you. Let's just discuss a little bit the deal and answer any questions.

Okay. Madhu, do you have a question?

So Pascal, on the point you made about the idea of introducing a stop codon and really kind of fully inactivating C3, I mean it seems like kind of a problem, right, because if you fully inactivate systemic C3, discuss this idea of like infection risk. And if it's gone, gone, like that feels like -- like how do you think about the management of infection risk in that context versus when you can transiently inhibit C3 in the kind of therapeutic setting by a small molecule inhibitor?

Well, if you think about it in the same context as siRNA, we believe siRNA can do something similar, except you might need to treat. But ideally, you do chronically, right? The disease we're thinking of is something you need to chronic like PNH as an example, but we want to go way beyond that. A good [ science-ing ], I mean, obviously, it isn't 100%. So there is already -- the Beam technology will allow you to probably be a lot more controlled in how you inhibit, the level you inhibit. How you deliver also is going to be key. If you go in the brain and the eye, you're never going to hit 100%, so we have a good understanding of the level of inhibition you will need to join the pharmacology you need for specific indications. So we're very confident that we can position that and leverage the strength, understanding the limitation of this technology.

And then the C3 gene structure is such that you can introduce potentially like a single stop codon on any one site and all splice forms getting active and all that kind of stuff. It's an agreeable question when thinking about editing is -- when you edit, usually in CRISPR, you're just going to blow up the gene versus if you're using base editing because, to your point, you hit a single site, if it gets spliced out, then it's like what you did didn't happen. So how do you think about the C3 gene structure? Is that amenable to...

Yes, I mean to your point, there are so many ways we can effectively be very specific how the effect you want. The other thing to think of C3 mutation and complement gene mutation, they are known, some of them are protective in diseases. So that's an area. So there's a lot to be done. It's 5 years. There's a lot of different approaches that's going to be explored. We're going to do animal models. We understand what -- to read the full potential of this technology to address the complement. And we're actually pretty confident we'll find good opportunities for great therapies.

Steve Seedhouse, Raymond James. So I just want to take a step back because you moved quick through that. Obviously, interesting collaboration. I want to clarify, does this encompass only editing complement targets, starting with C3? Or does it encompass novel base edit targets in combination with your broad pipeline that you laid out today or both of those things?

So the details on what we are going to do we're not going to be talking about today. But what is key here is that this is an exclusive agreement across all of complements, so not just complement factor C3. And we are going to be thinking, of course, in the context of combining that potentially with other things that we are doing. I think what I find interesting is if I think about gene editing and the complement pathways is, on one hand, you could kind of use kind of the things that we understand well and then the more kind of complicated work of resetting homeostatic systems. If we talk about the former, the beauty is that if you take, for example, patients with siRNA and you treat them for a couple of years, then you have established a pretty good safety database for what it means to suppress almost maximally, right, whatever comes out of the liver. You may have noted the difference between the messenger RNA, which disappeared 99% but still having about only 90% of the protein that is gone. That remaining 10% comes from somewhere else than in the liver. So if we're going to be editing the liver and when the liver regenerates, that edit will get communicated to all of its defenders as well, right? Imagine having a couple of years of solid siRNA safety data behind this with a robust efficacy and safety profile and then saying, why do we keep on giving siRNA. Just correct it once and for all, and now you can be on a once-a-month dosing with, for example, EMPAVELI to keep your control for the rest of your life. Justin?

Just maybe a question on the mRNA approach and sort of maybe potential readthrough then for this collaboration. Is there differences between how the presence of free-floating C5, which demonstrate that you couldn't achieve sort of a monotherapeutic benefit, could be slightly different if you have residual free-floating C3 and sort of comment to that?

That's certainly fair, right? I mean so what Justin is referring to is that Alnylam created a very potent -- as Lukas discussed earlier, a very potent siRNA approach for C5, were great preclinically, as a matter of fact. And then when it was tested in patients with PNH, the LDH values were not well controlled. And the question being could an siRNA approach with C3 not work on its own and does it necessarily need EMPAVELI on top of it, that is a fair question. We don't know the answer to that question. But kind of the more obvious answer is the one that we believe where the convertase activity, even when you have, for example, only 10% of C3 left, needs to be kept under control. Any other questions? There's not a lot standing between us -- or nothing standing between us and the Mint Juleps because you're in a Kentucky-born company's home here. So we have a little present for all of you outside. We have Mint Juleps. You can also stay as long as you want because we have a lot to celebrate. I'm going to just quickly wrap up a couple of things here. First of all, going back to the slide that we had at the beginning, in rare diseases, yes, EMPAVELI launches off to a strong start. The platform potential for EMPAVELI with 4 new registrational programs: the new molecular entities; the neurology; C3, that plays a key role in many neurodegenerative processes; and our effort to pioneer targeted C3 therapies. Then in ophthalmology, our optimism heading into the readout on the Phase III clinical trial where, on the monthly dose individuals, we have minimum effects from COVID-19. On every other month, that effect is a little bit larger. We'll see what it gives. But as Jeff outlined, we have no concerns as that relates to the approvability of the product and there too the new products in development. And if you put all of that together on a pipeline slide, then this is what Apellis represents today. And we very much look forward to the next couple of years to communicate how we do with all of this. And for the rest, thank you all for coming. Thank you for the people online that have been watching. The ones online will have to miss out on the Mint Juleps, unless you make one at home. And next step is September. Have a very good summer, and we look forward to the data on the Phase III GA readouts. Thank you.