Welcome. Thank you so much, all of you, for coming. This is a very special moment for us. Apellis is, as many of you know, a very young company. This is our first official R&D Day as a public company, and it's one that we're really enjoying. We got a beautiful location thanks to our IR specialists who discovered this place. Thank you so much, Alex. We hope you will enjoy it in the afternoon. We have some very special people here today with us to speak with you about the diseases that we are targeting. That is really why we are most excited about being here this afternoon, because at the end of the day, it is about patients. It is about trying to make a difference in the lives of these people. The physicians that treat these patients know that better than anybody else.
Patients themselves, obviously, when they give us testimony, it also reminds us of why we do what we do. Today we have the special privilege of having a great set of key opinion leaders with us that have treated patients with geographic atrophy, that will come here to speak about what this disease means. We also have two very special individuals here who are real patients: a patient with PNH who flew all the way over from Canada. Barry, thank you so much for joining us. Richard, who is a patient with geographic atrophy. Thank you so much, both of you, for joining us here today. We have an overview of, on one hand, the scientific realities that we are trying to target. On the other hand, the clinical data that we have generated.
Finally, what we have to look forward to in our phase III clinical trials, and afterwards, hopefully, when we make it to the market. We're going to start off, obviously, the forward-looking statements which you are all familiar with. An overview of our R&D day. First of all, we are going to dive into geographic atrophy after a brief introduction on the complement pathways. Within GA, what we want to do is, first of all, have a world-renowned expert, Usha Chakravarthy, who joined us from Belfast, to talk to you about what GA really is, because it's a disease for which there are no therapies and therefore poorly understood, but with a dramatic impact on the lives of patients.
We are going to have a testimony by our patient with geographic atrophy, Richard, who is going to talk to you about what it is to live with this disease. We will have an overview of the data in the FILLY clinical trial. The trial that we ran where we showed for the first time that we could reduce the growth of atrophy in these patients. We will have a presentation on the data there. We will also have, after that, a presentation by Jason Slakter, who will talk about the phase III clinical trial and what we attempt to do there. After that, we will have a brief break, we will dive into paroxysmal nocturnal hemoglobinuria.
First, a presentation by Pete Hillmen, who will talk about what the disease means, the mechanisms behind it, and the data that we have generated in treatment-naive patients with APL-2. We will then have a testimony by Barry about what it is like to live with PNH. Finally, Pete Hillmen will speak about the data that we have generated in the so-called PHAROAH trial, where we cohort those patients who used to be severely transfusion-dependent, and what happens when you add APL-2 on top of that treatment. Last but not least, we will have a brief overview of our early-stage pipeline. These are early clinical data with APL-2 in autoimmune hemolytic anemia, as well as in the complement-dependent nephropathies. There we have the great privilege of having with us Dr. Richard Glassock, who is a world-renowned expert on nephropathies.
We won't have a special presentation dedicated to it because of lack of data, but when we have questions, obviously, we will have his expertise to answer those. Taking off with this central pathway that we target called the complement pathway. As you can tell from this slide, it is quite complex. You have 30 to 40 interacting serine proteases, proteins that interact and react with each other and are really critically important in the balance of our immunity. To put a very simplistic slide of how you should view our immune system, there are probably two distinct sides to how we deal with invaders from our environment. On one hand, we have the innate immune system, you see there are molecular blasts, shock and awe, and that is kind of what happens with innate immunity.
We sense danger, we react to it, we hope that we survive, but there is no intelligence behind it. We don't try to differentiate between what is self and what is foreign. In adaptive immunity, we developed the ability to actually make that distinction, which cells belong to ourselves, which cells are foreign, and by nature, we will attack anything that is foreign. How did this come to be? This is a simplistic slide of the rise of adaptive immunity. You should imagine 400 million years ago, approximately around the Ordovician period in the Paleozoic, when we became jawed fish, we got infected with a retrovirus, and that retrovirus gave us the so-called recombination activating genes. These are simply stated bad copy machines.
These bad copy machines allow us to create the diversity in T cells and B cells that we need in order to create that adaptive immune system. While that evolved over 400 or hundreds of millions of years, complement was there to take care of business. The interplay and the interaction between adaptive and innate immunity and the guidance that complement played in the behavior of the adaptive immune system, we are only starting to understand, but we believe it is critically important. Needless to say, because of that phylogenetic history, the roles of complement are incredibly diverse all over the way in which adaptive immunity behaves. In spite of that, we only have a couple of approved complement inhibitors.
Three inhibitors that act at the level of C1. Obviously the great drug, SOLIRIS, which is currently the mainstay and the standard of care in patients with paroxysmal nocturnal hemoglobinuria. Now because of the fact that we target complement factor C3 centrally in the pathway and block all of the effects of complements regardless of what the source of activation is, and based on the initial data that we've generated, which you will again see much more on this afternoon, we have coined this term complement immunotherapy. It's a broad term. We don't mean anything special by it other than by inhibiting complements, we have an effect on immunity that is broad, applicable to many indications, not just the ones that you will hear about this afternoon.
Where we see ourselves at the beginning of a journey in a privileged place with the first C3 inhibitor in advanced development, and the possibility to explore what can be done. I think hopefully that you will agree with us at the end of this afternoon that the initial data that we've generated is truly intriguing and exciting. The key milestones for 2018. After we became public, we had to learn about discipline and providing timelines, so we tried to abide by those. What we said last year was that in the first half of this year, we would give you data on the 18-month efficacy in geographic atrophy. What does this refer to? In August of last year, we read out the primary endpoint in our 246 patients phase II geographic atrophy trial.
We stopped dosing patients for six months, and after those six months, which is the 18-month time period, we said, "Let's look whether the lesions, which we had shown to be able to reduce in growth, would start growing faster again." That was indeed the case. We also in April gave the first data on treatment-naive patients dosed with APL-2 and affected by paroxysmal nocturnal hemoglobinuria. These are patients that had never been treated with complement inhibitors, and we showed promise after one month of dosing. Today you will see an update on that expansion of our so-called PADDOCK trial.
We had patients where we tried to address the unmet need that is really our mainstay and the reason why we do what we do in PNH, where we had patients that were severely transfusion-dependent, really bad anemia, in spite of being on SOLIRIS, often at higher than normal dosing. We added APL-2 on top of SOLIRIS, and as you will see later today, had remarkable results in terms of normalizing these hemoglobin levels, in many cases, reducing the transfusion dependency. We said, "Well, based on the mechanism, C3 covers everything that C5 does, it should be possible to wean these patients off of SOLIRIS. They are probably still receiving SOLIRIS without reason." We will show you later today what happens when you do that. We also will have the first data in autoimmune hemolytic anemia.
These are hemolytic anemias where we have antibodies against certain receptors or proteins on our red blood cell surfaces. When these antibodies bind, we get a process that is actually quite similar to the reason why patients with PNH on SOLIRIS often don't respond well. It's a process called extravascular hemolysis. We'll dive deeper into that later. In autoimmune hemolytic anemia, split between cold agglutinin disease and warm antibody autoimmune hemolysis, we believe that C3 inhibition can also provide a significant therapeutic benefit. Without further ado, we are going to dive into the first chapter of the day, geographic atrophy, and I would like to, first of all, introduce you to Dr. Chakravarthy, who has joined us from Belfast. Thank you so much, Usha, for joining us here today. She will tell us about the disease burden and healthcare resource use and progression.
Thank you so much.
Thank you, Cedric. Well, it's an enormous pleasure to be here today. It's my remit to tell you a bit about geographic atrophy. I'm sure many of you will have done due diligence and learnt an awful lot about it. This is kind of an initial summary to this particular event. First of all, I want to make three points. One is that geographic atrophy is associated with very high levels of visual morbidity, and it impacts hugely on mobility and independence. It's a bilateral condition. It doesn't affect just one eye, it affects both eyes. From what we know now about geographic atrophy, we are aware that the proportions of eyes that progress to blindness is much greater than that which has been recorded in previous studies. There's two manifestations of age-related macular degeneration. That's the disease condition we're really talking about, AMD.
Those two manifestations, one is geographic atrophy and the other is choroidal neovascularization. These are the late-stage manifestations, and they're both visually disabling. We have some treatments that work reasonably well in choroidal neovascularization, the lay term being wet AMD, but nothing for geographic atrophy. I thought I'd start off by showing this slide just to show people what the eye looks like. In this panel of three images, this is what we see when we look into the eye with our microscopes, our ophthalmoscopes. This is the optic nerve, this is the macula, and this central spot, the red spot there, is at the fovea. This is the bit you use to read, write, and have fine discriminant vision. As we grow older, we get these yellowish lesions in the back of the eye. These are known as drusen. It's a marker for aging.
At this stage, the eye still has good vision. Unfortunately, these drusen accumulate gradually and fill up the macula. As the drusen burden load grows, various things happen in the eye. Two pathways can happen. One is wet AMD choroidal neovascularization. You see this patch of hemorrhage, and over here is the area of atrophy. Atrophy is exactly what it means. It means cell death. The tissues at the back of the eye and the macula consist of the neural retina, the retinal pigment epithelium supporting tissue. The choroid layer, which is a vascular layer that provides the nutrition. As we go on through the talk, you'll see some examples of what happens in geographic atrophy.
Patients who have geographic atrophy, even very small parts of the macula involved by this process of atrophy, will have difficulty with reading. They will experience problems with low light conditions. It's a major cause of blindness in the U.K. If you look at the proportions of people who are registered as blind, roughly a quarter of those will be due to geographic atrophy, and likewise in the U.S. As I said already, there are no approved treatments. There are many epidemiological studies, very well-conducted studies that sample people in the population. These are not patients, these are just people off the street, so to speak. Photographs are taken. You assess what are the reasons for sight impairment in these type of populations.
Variable prevalence rates have been reported. That's because all the previous studies have depended on the color fundus images of the retina. This doesn't give you the whole story. Nowadays, we have much better imaging modalities, which shows us these microscopic areas of atrophy that first develop and then progress. The annual incidence of geographic atrophy is approximately 1.6 cases per 1,000. That equates to around 150,000+ cases per year worldwide. These are the kind of images that we can now get in our clinics and even in epidemiological studies, non-invasively acquired. You shine a light through a specific instrument, and here you see the optic nerve, the retina. You see this little patch here, and as you go along, the patch increases in size. This is the transsectional cut through the retina.
Here you see this layer of nerve cells. These are the photoreceptors. These are the cells that really capture light and convert it into a neural signal that takes it to your brain and prepares the picture that you see when you look out of your eye. Here you see that this layer narrows. Over time, just gradually, the layer disappears away. Leaves a patch where there's no retinal pigment epithelium, no photoreceptors, and no choroidal blood vessels. That patch, if I were to shine a light on that very specific patch to try and get you to recognize that you wouldn't see the light signal because there's nothing there to capture this information and transmit it to your brain.
Imagine what it would be like if you had these patches growing in size, and eventually you are left with a large black spot that occupies your entire macula. It would be like putting a coin on your spectacle lens and trying to look through it, where you just see a big black spot. Wet macular degeneration, neovascular AMD, as we call it, is currently treated with drugs that reduce that exudative manifestations. Here is a case of a patient who had wet macular degeneration. You see on the OCT scan, which I have showed you before, a lumpy, bumpy feature of the retina, and over time has been treated with anti-VEGF agents, five years and then seven years. But what happens at seven years is, although we control the exudation, we have ended up with geographic atrophy, big patch of geographic atrophy.
This patient, who had maintained good sight for the first three to four years, is now sitting with hand movement vision in that eye. Because we wanted to understand better how geographic atrophy affects people, and because we were aware that geographic atrophy seems to be the default pathway in age-related macular degeneration. There is something I actually meant to say right at the very start. AMD is a condition that affects the older population. We are all growing older, and we are all atrophying in many different ways. Our knees are not the knees that they were 20, 30 years ago. Our skin is not the same.
It is a process of general atrophy going on, and AMD is a way in which atrophy is occurring in the macula of the eye, therefore, the GA bit or the element of it is the natural pathway, and wet AMD superimposed phenomenon on it. The extent of vision impact due to geographic atrophy has been underestimated, and the fact that the early forms of geographic atrophy may not have been recognized because of the imaging modalities that had been used in the past led us to conduct this study using the electronic medical record systems of the U.K., which is linked also to the imaging platforms that we have. We are able to go back and look at much more detail than we had ever previously been able to. This was a retrospective analysis of a clinical data set.
It was captured on Medisoft, which is an EMR system. There were 10 National Health Service clinics in the U.K. that contributed the data, and the data cut was made in February 2016 and covered the period 2000 to 2016. This is not a clinical trial, patients whose data were captured might have been on the system for four years, they might have come multiple times, or maybe only a couple of times, but regardless, we had sufficient data to look at the presence of geographic atrophy in these patients. We had a total of 80,000 cases, and we were interested in the group of patients who had a diagnosis of geographic atrophy in one or both eyes.
Our eligible GA cohort was around 4,500 approximately, of which we had just under 2,000 who had GA record in both eyes, another 1,600 or so who had a GA in one eye and wet AMD in the fellow eye, and the third group was GA in one eye and neither GA nor wet AMD in the fellow eye, but early features of AMD. We just wanted to see how these different groups behaved in terms of progression to sight loss. Here you will see that the 1,900 people who had GA in both eyes, we looked whether they were progressing to choroidal neovascularization, that's wet AMD. Then we had the 1,693 people who did not meet the U.K. definition of blindness. That is at least one eye with sufficiently good vision or sufficient vision that they weren't classified as blind.
We looked for progression to blindness, and also we looked at the rate at which they lost sight as measured on a specific eye chart. Then we looked at how many people were eligible to drive. Some 500 had sufficiently good sight in one eye at least that they were eligible to drive, and at what rate did they progress to eligibility or loss of eligibility to drive. If you look at the factors here, 8% of those who had GA only went on to develop choroidal neovascularization, wet AMD, in the space of just one year. The median time to progression was one year. Some 30% lost three lines on the visual chart, visual acuity chart. Some 40% lost two lines on the visual acuity chart.
This graph over here shows the trajectory of sight loss in the better eye and in the worse eye. Worse eye is by definition are worse than better eye, so the average visual acuity is 40 letters on the chart. I'll be showing you a picture of a chart shortly, so you'll understand what these numbers mean. The better eyes had an average vision of 60 letters, and as you can see, by the time you get out to 60 months, not everybody had that length of follow-up, but you can see how much the sight has dropped to 37 letters, and those of the worse eye had also dropped, but the trajectory is a little bit shallower. Roughly one-fifth to one-sixth of patients who were not eligible to be registered as blind became eligible for blind registration within a period of two years.
Two-thirds of those who were originally eligible to drive had lost eligibility to drive. That's a huge impact on people who are used to being independent. This is a case where you can see geographic atrophy, but there's an interesting phenomenon here. The center part is spared for a prolonged period of time. On a visual acuity chart, because you're just using that center part of your retina to look at individual letters on a chart, you do not progress on the chart scale. Here you can see somebody where there are two islands of atrophy, and they eventually coalesce to form this big patch. Whereby the space of four years, this patient has lost all ability to see and has got a big blank spot in the center of patient.
Doesn't mean to say that this person is a great deal better off than the person shown above, because if you look at this person, you see that they've got a big scotoma part where they can't see, and they've only got a little bit of tunnel vision. If you sort of make a little tiny pinprick-type hole in the fingers of your hand and look through it and see how much reading you can achieve using your little spot of sight, you'll be surprised how incapacitating it is. This is the kind of charts that we use to measure sight. If somebody has got geographic atrophy as a patch, they can find their way down this chart and be able to read that letter C, and you can say, "Oh, that's your sight.
You've got 20/40 vision." In fact, when they've got another patch of atrophy, they might only see one half of the chart. They can still wiggle their way down to that C there. What happens when they try to read this kind of material where you have to have contextual information, where you're going to have to read words and sentences? Right. A lot of that will disappear, and what's worse is that they will be able to get maybe a bit of my, maybe a fat and a me, and to help carry. Doesn't make any sense. Reading becomes immensely difficult for people who have geographic atrophy. Their retina is really in a moth-eaten state. There's little patches missing, and trying to make sense of sentences and words is almost impossible.
There's work from Janet Sunness, who is a retina specialist in the U.S., she's looked at quite a small group of people, just 55 people. Just about very high proportions of them reported huge difficulty with reading, hazy vision, inability to see faces, recognize people, finding signs, and simply persons with geographic atrophy could not function in a dim environment like the sort that you encounter when you go into a cinema or somewhere with or even a restaurant. My God, nowadays, the restaurants have such dim lighting, you can't see the menu, you can't see anything. Think about these poor people who have even very limited amounts of geographic atrophy. My key takeaway message is that GA is a progressive disorder. It's associated with high levels of vision impairment and impacts on mobility and independence.
From what we know from our UK EMR, which covered a huge number of people, proportion of eyes progressing to blindness is much greater than we had anticipated or thought of. GA and CNV wet AMD are manifestations of the same disorder, but with very specific temporal relationships. Thank you for your attention.
Thank you so much, Usha. Thank you so much, Usha. This is truly tremendous work in terms of understanding this disease better. Next we are going to ask Mr. Robert Schonfeld to come and join us, and he's a patient of Dr. Slakter, who's here with us, and has kindly agreed to give us a bit of a sense of what it's like to live with geographic atrophy. Mr. Schonfeld has Stargardt disease, which is an early onset form of geographic atrophy. But with the same clinical implications of what that means. I want to thank you so much for joining us today.
Thank you.
Thank you.
Afternoon. This is more science than I've been exposed to since junior high biology class. A unique experience for me. I would've brought some notes, but I can't read them, so there was no point in doing that. I was thinking of telling a joke to start off, but my wife said, "Don't come home if you do that." We're gonna dive right in. I was asked to join you this afternoon, to give you a very brief idea of what it's like to experience this condition from the inside looking out. I first received a diagnosis in about 1984. I had grown tired of hearing my family eye doctor mumble into his dictaphone about drusen and fundus and all these things without explaining to me what they were, and just patting me on the back and telling me to say hello to my parents.
I asked for a referral. That referral was Dr. Lawrence Yannuzzi, I went to see him. Again, I believe it was 1984. After my first visit, his exact words to me were, "I have good news and bad news." "Bad news first, please." He said, "You have macular degeneration." "What's the good news?" "The good news, it's dry macular degeneration, it's not manifesting itself, most people don't know that they have it, most of them never will. You're in pretty good shape for now. Keep an eye on it. Come and see us every so often, nice to meet you." That was about 15 years until it did start to manifest itself, when one day I noticed a little twist in that grid that Dr. Yannuzzi gives everybody.
There was a little twist right in the center, I panicked at the sight of that I phoned VRM Dr. Yannuzzi was not in, fortunately Jason Slakter was, he has been my ophthalmologist ever since, as far as I'm concerned, he is not only a great ophthalmologist, but he is also a saint. If you're in my position, it's a lot easier to understand why that's the case. My atrophies, the things the doctor said are quite interesting. My atrophies have resulted in, at the moment, a very small preserved chamber, as it's called, in my left eye only. Very small, less than 5%. It is through this 5%, which Jason describes as like looking through a straw with one eye closed. Although nowadays it's more like a swizzle stick than a straw.
It is through this tiny little preserved chamber that I do everything. I read two characters at a time at 18 point font size. I can see if I struggle to make eye contact, I can see one half of one eye of the person I'm facing, the white and a little bit of the boundary of the eyeball, at a distance of about 18 inches. Other than that, my central vision is completely gone. If you want to have some idea of what that's like, hold your fists up to your face like this. Are you doing it? No taking them down. No. You have to leave them there. No looking around. No nothing. See, you can't do it. You can't do it. You can't do it for more than a minute. You can't do it for more than 10 seconds. Why would you?
That's what I'm faced with. In terms of the other effects that it has, I had to surrender my driver's license. I called the DMV in New York City, which is a surreal experience under any circumstances. I said, "I'd like to surrender my driver's license and get a New York State non-driver's photo ID." The lady said, "What?" I said, "I'd like to sur-" "Why do you want to do that?" "Well, because I'm blind." In fact, I had nearly driven off the George Washington Bridge in a rainstorm the week before, which is what convinced me to make the call. She said to me, honest to God, this happened. She said, "Who says you're blind?" I said, "Well, my doctor." She laughed. She laughed. She said, again, her exact words, "Your doctor doesn't decide if you're blind.
I decide if you're blind." I told you it was a surreal institution. I did ultimately manage to get that New York State non-driver's photo ID. I have figured out to this day how to read only on the laptop screen. I can't read anything that's in front of me two characters at a time like the eye chart that the doctor showed. I have corrected vision in that tiny little spot of 20/30. When I go every six months, it's a little game to see how low on the chart I can go. I tell people. I spend an hour a day reading Twitter. Why would I do that? Well, it's like going to the gym for my eyes. It's exercise. I'm stubborn about it. Facial recognition, out of the question.
I have to ask people that I've known for 35 and 40 years, "Please, when you see me, say, 'Hi, Robert. It's Harry.'" I say, "If you do that two or three times, I'll figure out with all of my peripheral vision and all of the cooperation of my brain that the, as the Italians say, the figura that you present, your presentation will tell me that it's Harry, even though I can't see you." I must say, most people are very cooperative about that. As far as my work goes, I was a curator. I was a consulting curator. I grew up in the art world. I grew up in the art business. I was an art advisor. I hasten to say that business is still open. My wife, who was always better at it than I ever was, still takes care of our clients.
If any of you need any art advisory work done, you can still get ahold of us. For me, it's over. I don't have any visual acuity in my central vision except that teeny tiny thing, which in addition to being so small, is now pretty hazy. It's quite difficult for me. Forced retirement. When you're in the art business, you don't think about retiring. Why would you? What are you going to retire from? There's nothing to retire from. I was forced to retire. That was unpleasant. If you ask me, am I frustrated that nothing has been available to me? Jason Slakter, who has a brilliant manner with his patients, will tell you himself that one of the things he thinks about is that he has nothing to offer. How does one deal with this? It is frustrating.
Am I angry about it? You better believe it. Does it result in depression? Yes, it does. You get a little extra two for the price of one with these diseases. Neither of which hurts, by the way. No physical pain. That adds to the mental difficulty of coping with these diseases. It's an honor for me to be among such a dedicated, motivated, and talented group of people who are working so hard, as far as I'm concerned, on my behalf. Thank you for having me. It's been my pleasure.
Thank you so much, Robert, for that. This is what we do it for. Before we move on to the data of the FILLY trial, our phase II clinical trial, I thought I would take one minute to take you through a little video. The story of complement in ophthalmology, and specifically in macular degeneration, started around 2005, which any retinal specialist will tell you was one of those grand years in the history of ophthalmology. It was the year that the first anti-VEGF came out, and it was the year in which the first association was established between all of these snips in the complement pathways and macular degeneration. Since then, we've made a lot of progress, lots of trials, lots of preclinical research. We still don't really fully know why complement plays a role in this disease, if any.
We have data that make us believe, but we don't really understand the pathogenic mechanism completely yet. Through the data that we gathered, both in PNH as well as in geographic atrophy, we have assembled a disease hypothesis, something where the pieces of the puzzle fit together. Is this the truth, or is this truly what is going on? Maybe yes, maybe no. The evidence is quite compelling. That's what I want to briefly take you through. Within the complement pathways, everybody likes to focus on the nuclear weapon that I showed you earlier. You have an infection, everything goes gangbusters. That is not what happens every day. We are exposed as healthy, normal individuals throughout every minute of every day to complement depositing itself on all of the surfaces in our body.
That baseline deposition, you should think of it as painting of all of the cells in your body with complement, is a really, really important piece of our biology. It may sound boring, but it becomes far less boring when you think about the implications when cells forget or stop to clean up the trash from their cell surface. The one thing I would like you to remember about C3b, which is what we discovered through our work in PNH, is that once that central protein in the complement pathways binds itself covalently and irreversibly to a cell surface, there's only one way for that cell to get rid of that product, and that is through a process called endocytosis. Which means that the cell essentially creates a fold in the membrane, brings that product inside, and then digests it.
When there is something that goes wrong and that digestion doesn't go well, that is a problem. We believe that in the retina, it is especially problematic and linked to an energy deficit. That's what I'm going to briefly show you in the next video. What you see here is a cell. It's any cell in our body, all 13 trillion cells exposed to C3b binding itself irreversibly to the cell surface. We inactivate that product, and we endocytose it, we gobble it up. Imagine this being a retinal cell sitting there. They look very different, but bear with me for a second, right? C3b binds, we endocytose it. You see the battery in the middle. That is the cell in a state of energy. It has enough energy to clean up the paint from the cell surface, and everyone is happy.
As we grow older, we get more C3. We get more C3 in the cerebrospinal fluid. We get more C3 in the retina as well, meaning that there is more painting going on of the cells. Meaning that the cells have to clean up more through endocytosis. Meaning that the energy requirements to do that become higher as well. At some point, these retinal cells go into a state of being energetically stretched, and they start neglecting the cleanup of that C3 product on the cell surface. You could say, "Who cares?" Well, that is a big deal, because in the retina, as in the brain, you have microglia and mononuclear cells floating around, that when they detect that product on the cell surface, they will phagocytose those cells.
That is what we believe happens on the borders of these geographic atrophy lesions that Usha showed to us earlier. What APL-2 does, and I would love to tell you that this was by design, but I think we really got very lucky, is that it binds to C3 before C3b binds itself irreversibly to the cell surface. By doing that, what it de facto does is it allows these cells that are energetically stressed and trying to keep up what comes in, gives them an opportunity to go into an endocytosis surplus situation and clean up their cell surface and become more homeostatically balanced again. That is something that we believe is critically important in the homeostatic process and the findings that we discovered in the FILLY trial that Jeffrey Heier is going to talk about next.
As many of you know, in our trial, we saw a significant reduction in the growth of atrophy, but it was associated with leakage in the retina. New onset exudations, which we believe is in part driven by these glial elements, these cells, these mononuclear cells that will start secreting VEGF in an effort to repair. With that introduction, I would like to introduce the great Jeffrey Heier, who is joining us from Boston. Many of you are familiar with his work and his background, and we're so honored to have you. Thank you so much, Jeff.
Thank you, Cedric. Thank you, Cedric. More importantly, I'd like to thank Mr. Schonfeld for so eloquently and honestly describing his experience. As Usha, Jason, and I can tell you, patients like Mr. Schonfeld occupy our clinics every day. It's extremely frustrating that to date, we don't have anything we can do to help them. It's why we're excited to be here because we're hopeful that this work is going to change that. It's been an interesting few years in retina. We've seen many promising pathways undergo critical investigation and not develop, not reach their primary endpoints. We've seen studies that unfortunately have failed. Studies that have looked at combination therapy of anti-PDGF and anti-VEGF therapy, anti-Ang2, anti-VEGF co-formulation that had a large phase II program that didn't meet its endpoint.
More recently, and one you're probably all very familiar with, was lampalizumab's inhibition of complement factor D, which didn't demonstrate efficacy. What you're hearing today is fortunately, there continue to be promising pathways on the horizon, we're going to talk about that now. We have some key takeaways that we want you to remember from this presentation, the first is that APL-2 reduced the progression of GA secondary to age-related macular degeneration in what is the largest Phase II GA trial to date, 246 subjects. These results correlated to treatment frequency with increasing effect size over time, our confidence in these was increased from the results of intra-patient controls in those patients who had bilateral GA, but only one eye was treated. Ultimately, upon study completion, when APL-2 was discontinued, the treatment effect declined but was still present.
What you've certainly taken away from Cedric and Usha's presentations is that the complement pathway and its relationship to geographic atrophy is extremely complicated. The complement system can be activated by three pathways, lectin, classical, and the alternative pathway, all which ultimately end at C3's activation or the breakup of C3 into its active component, C3a and C3b. In age-related macular degeneration, the presence of drusen and oxidative stress lead to an overactivation of the complement system, from that, what we end up seeing is damage to the RPE, deterioration of the local environment from a pro-inflammatory response. We've seen other attempts to impact this, we mentioned factor D. Lampalizumab inhibited factor D, this only worked on the alternative pathway and didn't demonstrate efficacy.
We've also seen previous studies looked at C5, as you see in the bottom of the cascade here, although there have been both intravitreal and systemic attempts at this, these also didn't demonstrate efficacy. There's another study ongoing in early phase right now. There's even a study looking at the end here, the MAC or membrane attack complex, which we don't have data on now. APL-2 works centrally by stopping C3 right at its common convergence of the three pathways. Hopefully, by doing this, we're blocking all of the downstream effects of those three pathways. Let's talk about the FILLY Phase II study in GA. This was a study that randomized patients to sham injections, to APL-2 administered every other month, or to APL-2 injected every month. As you can see, there were roughly 80 patients in each of these three groups.
This shows the timeline of the study, patients were imaged extensively at baseline months two, six, and 12. 12 was the endpoint of the study. Then again at 18 months, six months after the study drug was stopped. The primary efficacy endpoint is the change in geographic atrophy lesion size from baseline to month 12, the primary safety endpoint was the number and severity of local and systemic treatment emergent adverse events. The baseline characteristics are shown here, they're typical of a study in geographic atrophy and macular degeneration. In general, they were well-matched. You see the number of patients with bilateral GA ranged from 82%-90%. You see the history of CNV in the fellow eye, little bit of difference here, ranging from 35%-42% in the APL-2 monthly group, the lesion size and visual acuity scores were well-matched as well.
This is one of the major take-home points here. This shows APL-2 slowing GA growth at 12 months. What we're showing here is the square root. There are two ways we often look at this. One is the absolute rate of change or the amount of change at 12 months. The other is the square root. When you look at studies, these correlate very closely. The reason square root is often used is it's believed this accounts for disparities in baseline lesion growth. Obviously, smaller lesions will grow at one rate. Larger lesions will grow a certain amount, not at a rate. The rates are often the same. This helps to account for that difference. What you see is in the sham group, the square root was 0.35 millimeters. I'll show you that this correlates well with other studies.
In the APL-2 every other month, it was 0.28. The APL-2 monthly, it was 0.25. The difference between sham and APL-2 monthly was 29% with a p-value of 0.008. Becomes even more interesting when you look at the change in lesion growth as separated by time, breaking it into six-month intervals. Why would we do that? Well, it stands to reason that for this drug to have an effect, there's probably some component of the disease that's already on its way. It makes sense that a little bit later after the drug's been active, you might see more of an effect. In fact, that's what you see here. If you look at the first blocks at six months, you can see sham APL-2 every other month APL-2 monthly look very similar.
When you look at the second six months, you see fairly significant differences. The sham growth is similar to the first six months. The APL-2 every other month clearly is less. The APL-2 every month is even more impressive in the change. I said it was important to look at the sham groups and the control groups to understand what patients you're studying and to make sure they follow the natural history that you would expect to see in the disease. As we look here at the bottom, we're showing the data from the lampalizumab phase III study. What you see is when we take the square root in those studies, the numbers are virtually the same, 0.34, 0.35 millimeters, identical to the sham group in the FILLY study.
One of the other things that was looked at was after treatment ended, after the main treatment phase was over, what happened to the growth? What you see here is the curves, which between 6 and 12 months were diverging, now become parallel again. Yet the treatment benefit remains. It's interesting to see that you do maintain the treatment benefit, once the drug is stopped, the growth rates are similar, again, giving more confidence that the treatment is actually having an effect. Here again, we look at lesion growth in these six-month blocks. We previously looked at the difference from 6 to 12. Now when you look at the difference from 12 to 18, they're starting to enlarge again and get closer to that seen in the sham control arm.
One other area to look at was in those patients who had bilateral GA, but only one eye was getting treated, of course, in the study. How did the two eyes differ? In the sham arm, there was no difference, as we would expect. In the APL-2 every other month arm, there was a difference, 10%. When we looked at the APL-2 monthly arm, that difference increased to 23%, again, giving us confidence that we're seeing an effect not just measured between patients, but within the same patient with the different treated eyes. You heard Cedric mention there was an interesting finding in this study, and this was the new onset of exudation. This is the data at 18 months. If you look at the top in the APL-2 monthly, there were 18 patients who had evidence of exudation or 21%.
In the every other month, it was seven- patients or 9%. In the sham arm, it was only one patient or 1%. I do want to temper this by making sure everybody remembers Usha's talk. We expect the sham arm to have a certain percentage of growth. Whether that's 6%, 8%, 10, somewhere in that range, we would expect there to be growth in that arm, and we didn't see it here. It's because they're small numbers at this stage. When we look at patients who had CNV, choroidal neovascularization in the fellow eye, this data becomes even further different. What you see here are subjects with wet AMD in the study eye in the APL-2 monthly group. This was 13 patients or 36%. In the APL-2 every other month, it was five patients or 18%. Again, in the sham, we didn't see any.
When we look at the patients who had no CNV, no choroidal neovascularization in the fellow eye, these rates were much lower, 10% in the monthly, 4% in the every other month, and 2% in the sham. These numbers are more in line with what we expect from the natural history. It becomes even more interesting when we look at the type of exudation that was seen and try to study that. If you look on the left, what you see here, this is an actual patient from the study, and we measure the exudation by seeing these small cystic areas here that are suggestive of fluid. As you can see, there's a little bit there and there's a little bit of thickening. I want you to compare that to the typical type of onset of choroidal neovascularization we see in wet AMD patients.
This is typically what we see, far significant thickening, more fluid. While not every case is like this is characteristic of what we see with new onset CNV, and this was characteristic of many of the patients in the study. The extent of the CNV, the robustness of it appeared to be tempered, and whether that's by catching it early or actually an impact of the drug is something that we're going to study further, and Jason may talk to it, and we may talk to it in the sit-down session. Again, the key takeaways right here. APL-2 reduce the progression of GA secondary to AMD in the largest phase II GA trial to date. The results correlated to treatment frequency, and as we showed, there was an increasing effect size over time.
Our confidence in this was bolstered by the intra-patient controls of those patients who had bilateral GA. Finally, once APL-2 was discontinued, once the study treatment phase was ended, the treatment effect declined, the benefit was still seen. Thank you.
Thank you so much. Thank you so much, Jeff. To round up our geographic atrophy session, the one and only Dr. Jason Slakter. I have to say this, Jason was the very first retinal specialist that I spoke with when we started trying to make a difference in this disease. You've been an incredible friend to us.
Well.
Thank you so much.
Thank you. It is exciting to be here with you today for a number of reasons, not the least of which is this crazy, then younger guy came up to me in 2005, February to be exact, three months before the first publication was ever made relating complement to AMD, and he sat down with me on a planter at a hotel in Miami and said, "I have this idea that complement is important in AMD." He was right. He was just way ahead of time. Now, it's been a long time since then, and a lot of work has been put in. I have to tell you, I've been practicing ophthalmology as a retina specialist more than 30 years.
I don't hide that fact even though it gives away my age, because LinkedIn updates people every year, thank you very much, and says, "Congratulate you on how many years," which is such a nice thing to have. I've been doing it a long time. I remember when I started, every AMD patient that we saw was in the same boat. If you had exudative AMD, and fortunately, my colleagues are younger, but not that much younger, so they remember those days where people walked into your office, and whether they had atrophy or they had CNV, we had no treatments that were effective. We told our patients, "I'm sorry, there's nothing I can do." That world changed.
Somewhere around 2005, we got anti-VEGF therapy for exudative disease, now we take for granted the fact that people with exudative disease come to our office, and we have a way to manage it. We've also had to face the fact that since 2005, we continue to tell our patients that, "Sorry, there's nothing I can do when it comes to geographic atrophy." Robert, who so eloquently told you what it's like, is not alone. Nothing personal, I wish you were the only one. It's every day in every retina specialist office around the world, we deal with this problem.
It is a pleasure to be able to be talking about a phase III trial based upon very powerful phase II data that gives me the hope that if this study is positive, we will turn the page in dry AMD as well and be able to offer something to our patients. Again, my pleasure to take you through this. Real easy takeaways for me today. The company is on track to initiate the phase III registration program this year, second half of 2018. In the phase III trial, it will be the same population that was enrolled in the phase II FILLY trial. No change in the population.
The primary endpoint will be the change in geographic atrophy as measured on fundus autofluorescence at month 12, this trial will include a number of functional secondary endpoints that we've already heard today are critical in understanding the impact of this therapy on the patients being treated. These slides show you the overview of the phase III program. There are two large multinational clinical trials that will make up this phase III registration program. As stated, patients will have geographic atrophy secondary to age-related macular degeneration. The endpoint will be the change in atrophy as noted on fundus autofluorescence at month 12, although it is a two-year study. This is a double-masked clinical trial randomized in a 2-to-1 fashion. There are four arms. One arm receives active drug monthly. Second arm receives the active APL-2 every other month for the duration of the study.
There are the matched sham injection procedures, either monthly or every other month to control the study. The drug will be the same as in phase II, 15 milligrams of active APL-2 and 100 microliters or a sham injection. Each of the two clinical trials will enroll 600 patients in 100 centers worldwide for a total program of 1,200 patients in this registration project. As stated again and again, there are no changes in the inclusion or exclusion criteria going into this phase III clinical program. The key criteria remain visual acuity better than 24 letters or 23/20 on a Snellen chart. There are parameters around the size of the GA between two and a half and 17 and a half square millimeters.
If you have multifocal GA, which is allowed, you have to have at least one area of atrophy greater than a half a disc area. When you do autofluorescence imaging, patients can have these little bright spots around the area of atrophy indicative of disease activity, meaning progression, and the patients can have any pattern that's been described as long as they have some evidence of these abnormalities. Patients with a normal autofluorescence pattern around the atrophy are excluded. Very importantly, as in the FILLY trial, the presence of neovascularization in the fellow eye is not exclusionary, and patients will be enrolled as long as the study eye meets these criteria. The endpoint has already been mentioned. Change in the area of atrophy at month 12 as measured on the fundus autofluorescence.
We have added additional visual acuity and functional endpoints, including best corrected acuity, low luminance best-corrected acuity, low luminance deficits, reading speed, microperimetry, visual function questionnaire, and a functional reading independence index, all of which will be looking at the impact of the atrophic changes on a patient's life. There are some changes, but I like the title of the slide because it's improvements in the trial. This is a double-masked trial. Everyone interacting with the patient, and the patient, and the vision examiner, and the reading center, which by the way, will be the same reading center evaluating the primary endpoint as happened in the phase II trial, will all be masked to treatment assignment.
There is one treating physician in each office that administers either the drug or the sham injection, but as with most of the clinical trials done now, that doctor is not allowed to interact with the patient other than performing the act of giving the injection. There will be additional time points. We've included additional imaging points, which are very critical in understanding the entire progress of the disease over the two years. There'll be two functional assessments of reading speed and microperimetry, as mentioned, two functional patient-related outcomes, and very importantly in this trial, as opposed to the FILLY trial, if a patient does have an identified conversion to active exudative disease, they will remain in the trial. They will continue to receive their assigned study drug and will be managed with anti-VEGF therapy.
The visual function endpoints have been added, as I think you've already gotten the message already from Usha and from Robert about looking at how this disease impacts a patient's function. You'll be looking at reading speed, which is the speed with which someone can read the text. We know that when there are scotomas and blocked spots, it slows down that process. Be looking at microperimetry, which is a machine way to look at these so-called blind spots in vision. Importantly, there are also what we call patient-reported outcomes, both for distance and near acuity. These are ways to find out what impact on a person's life these visual deficits are having, and they are included across the board in this clinical trial.
Finally, and importantly, when an investigator identifies the possibility of new exudative disease occurring in this patient with dry AMD and atrophy, the patient will undergo multiple imaging modalities to confirm that indeed, this is an active exudative state. This will include fluorescein angiography and OCT angiography in sites that have it. Once it's been confirmed conclusively that active exudation is taking place, as I said before, the patient remains in the trial. They don't change their treatment assignment, but they initiate anti-VEGF therapy to control the exudation and see how they do at the end of the study. The key takeaways, as I said to start, were real easy. On track to start in the second half of this year. Same populations. We saw the exciting data that Jeff presented earlier.
The primary endpoint remains the change in atrophic area over the course of time, with a primary readout at month 12, the addition of very critical secondary endpoints look at patient function and the impact on the disease. Thank you very much.
Thank you so much, Jason. We are now going to have Sorry? Yes, let's do that, please. We are going to have a brief panel discussion. Thank you. All right. Excellent. All right. Well, what I thought we would do is, when we go on the road and we meet with investors, we obviously get often the same questions. We are very excited about the FILLY trial. The elements within the FILLY trial that give people pause are obviously these emergences of these new-onset exudations. What does this mean? I gave you a possible explanation through the hypothesis that we have, I think most importantly, it's important to contextualize the impact on vision, the impact on patients of these new-onset exudations, because we have concluded that they are quite distinct from what you would otherwise see in a patient that is newly diagnosed with so-called wet AMD.
maybe Jeff, you talked about the FILLY trial. Would you maybe mind elaborating on that a little more?
I think it's important to recognize that if you have somebody who has CNV, if you have somebody who has geographic atrophy, what we've heard now, first of all, is there's a treatment for CNV. There's not a treatment for geographic atrophy. Even separate from the idea that we think these lesions are less robust than what we're seeing in conventional new-onset CNV, even if they're identical, we have a treatment for those. We know from our treatments of wet AMD that if we treat patients regularly with anti-VEGF therapy, that right at the start, 80% of those patients don't lose any vision, and most of them gain vision. With GA, we don't have any options like that. I would contend that most patients, if not 100% of patients, I'll defer to Mr. Schonfeld to ask him that.
If you ask them which you would want, the answer always used to be, "Oh, I want dry AMD," because wet AMD or choroidal neovascularization is bad. We now have good treatments for that, and our patients who have geographic atrophy actually get frustrated. They say, "I thought you said dry was supposed to be good. This is terrible. Why can't I have wet?
Mr. Schonfeld, do you want to comment on which you'd prefer?
I will say this, I get asked very often, "What do you have? And I thought you had macular degeneration." I said, "Well, that's what I have." Say, "Well, my friend has that, and she's getting injections, and she's much better." I said, "Well, that's not what I have." "You said that's what you have." The upshot for someone looking from the inside out is it, and someone wrote about this in "The New York Times," I wish I could claim credit for this line, but I can't. Recently talking about vision loss. When you go blind, you get kicked off the team. People aren't especially interested in including you in things, and so the availability of any sort of treatment that can keep you on the team is something that would be very desirable. Is that a fair answer?
Very fair.
Thank you so much, Robert.
Thank you.
Usha, you did this incredibly thorough analysis of the NHS database. Particularly talking about the background because we had this one case in our sham control group. Maybe if you could briefly elaborate on your findings in England, of course, not in the U.S., but what you consider to be a normal progression rate within these patients.
Patients who have geographic atrophy, the classical type of geographic atrophy is big patches of atrophy, will develop CNV at a slightly lower rate than those people who have just drusen or have wet AMD in one eye and some minor degrees of small areas of atrophy in the fellow eye. If it does seem as though the angiogenic repair potential of eyes that have large patches of atrophy is dramatically reduced. The point that you made, Cedric, was that in the mechanisms that you postulated, because I was actually very excited when your data came out because I thought, for goodness' sake, this is the first time a drug is actually working.
The fact that there was some degree of exudation happening suggested to me that that angiogenic repair switch was actually beginning to reassert itself almost, and that this indicated to me that your drug was working as opposed to all the other drugs that failed in the market previously. I do believe that GA is the default pathway in the eye. And okay, we are throwing in these anti-VEGF drugs month after month, after month, and then seven years down the line, we have this mega patch of atrophy there. Although we are controlling the immediate functional consequences of exudative AMD, which is very dramatic, you're not preventing the progression of geographic atrophy.
When I saw those little bits of exudation that was seen in the cases that you've shown so far, I thought, "Well, actually, yeah. Well, we can control that exudation as long as we can control both." I think your drug is giving us that potential to control the atrophy, and we have anti-VEGF that will control the exudation, then that has to be a win-win situation.
Thank you. I would like to spend most of the time interactively. Those are the important points that I wanted to convey to you because obviously when we saw these first exudations, we took this very seriously. We were concerned, and wanted to make sure that this was not a safety issue for patients. I think it's important to mention that after we did the thorough analysis, also presented it to our key opinion leaders and the great physicians that we work with, but also presented it to the regulatory organizations, because of the nature of what was observed, this was not considered to be a safety issue for patients. I think we took that very seriously. Once that was established, we became curious about the mechanism that was going on.
We don't know the answer yet, but I think that we've well designed the phase III to hopefully get more answers and understand this disease better. I want to use the remainder of the time to answer your questions, which are far more important. We have microphones. Only one? Good. Two. Raise your hand if you're interested in asking a question from our panelists.
One over there.
Yeah.
Hi, this is Madhu Kumar from B. Riley FBR. Really handful of questions. First one is about the FILLY data and this effect happening the 6 to 12-month timeframe. Is it strictly a pharmacodynamic explanation for why the effects shift after 6 months? What are your thoughts, the panel, the thoughts on the cause of a effect over a 6 to 12-month time span?
Can we do it or I-.
I-.
Go ahead.
I think once again, you've touched on the very simple complement inhibition system. Complement is so complicated, and it stands to reason that at least to some degree, at day zero, there's a certain degree of apoptosis. There's a certain degree of cell death that you just can't impact. Starting treatment there, you're not going to see any benefit. It's different than anti-VEGF therapy where we see effects at day one.
I think, to me at least, it makes sense that those cells that are predestined to die because their extent of damage is already there, they're going to die. You're going to see the benefits start to occur at some timeframe later. It may be it's not 6 to 12 months. It may be if you looked at 3 to 6, there's a difference, or 5 to 10. It's the concept that there's some delay before you actually see the treatment effect. Jason, did you?
I think that's 100%. Remember, when we measure atrophy, we're measuring dead cells. We're only measuring cells that have died and disappeared on the imaging. When you enroll patients, remember, we're enrolling people with known changes that got these hyperautofluorescence patterns. We know the cells are sick. They're just too far gone, as Jeff pointed out. You just can't expect to resurrect a cell that's on its way to die. What we can do is protect the cells that have a chance to survive and the healthy ones next to it. That's why it would almost be surprising if you didn't see that. That was one of the things when I saw the data that gave me the sense that that seems real.
To expect you to take a drug, initiate therapy, and from day one, suddenly change the growth rate when we all know some of these cells are destined to die, that would have been worrisome. To see this type of pattern is very reassuring that these are real biologic effects going on.
You also mentioned the lampalizumab phase III. Beyond just differences in how that drug worked in phase II and phase III versus the FILLY trial, are there things you learned from the phase III studies of lampalizumab that have been important for the trial design for DERBY and OAKS, or for trial conduct that have helped with the phase III design for APL-2?
Yes, a lot. Some of the small changes that occurred between phase II and phase III are, for example, the difference from going from the square root to the absolute lesion size. As Jeff outlined earlier, we use the square root because when you have an area, it's pi R-squared, and when you have a patient with an initial lesion size of, for example, four disc areas and a patient with one, they both progress at 10%, the patient with four lesion or four disc areas will contribute four times more to your ultimate outcome. That's why we took the square root, because that linearizes the data. The paper that did that analysis on natural history was not considered sufficient validation by the FDA. We went to absolute lesion sizes in the phase III, which is similar to what was done with the lampalizumab trial.
When we did a post-hoc analysis in our phase II clinical trial, that even tended to give a larger benefit than if you did the square root analysis. As it relates to the sham control, we also looked at the lampalizumab data, of course, and the sham control in the lampalizumab clinical trial, the MAHALO study. If anything progressed a little bit faster than we saw in our study, that too gave us confidence that the sham was good. I think most importantly, in our trial, beyond trying to really understand or grasp as to what the difference is between factor D and factor C3, is just the data by itself.
In our study, not only did we meet statistical significance on both of the groups, for me, the most telling piece is the patient that had bilateral geographic atrophy. Not only did we see that trend for an effect in every other month and the real effect in monthly, you're talking here about comparing the treated eye to a brand new set of control eyes. Those contralateral eyes were not part of any other analysis. There, too, we saw in the first six months, very little effects on one eye versus the other, and most of it kicking in in the second six-month period, with about a 40% difference between the treated eye and the contralateral eye in the same patients when you look from month six to month 12.
You look at that data set and then compare it to what was observed in MAHALO, which at the end of the day, were the data that led to CHROMA and SPECTRI. There, what we had was an unfortunate event, which really was driven by about 15-17 patients, where a genetic snip that was present in about half of the patients, and when you group those patients together in the control group, seems to progress faster than the non-genetic other controls. What the drug really seemed to do was to take those faster progressors and bring them back to the baseline. Because this snip was in the alternative pathway of complement, and because Genentech was developing an alternative pathway complement inhibitor, they thought that was a good match.
Importantly, between the readout from MAHALO and the readout from CHROMA and SPECTRI, other investigators looked at GA studies and also looked at this particular SNP to find out if that faster rate of progression was something that was normal. None of these studies could actually show that. Even before the readout of CHROMA and SPECTRI, I think that generated a lot of skepticism as it relates to the readout.
If I could just say one thing. To me, it was extremely reassuring to see the control arm, the growth rate in CHROMA and SPECTRI, because you're talking almost 2,000 patients, and a large proportion of those were control. I feel like so many early-phase studies are compromised by that control arm, where the control arm just doesn't behave as you would expect. Look at the anti-PDGF studies.
Yeah.
The control arm ultimately behaved exactly as the natural history suggested, and it was invalid. Here, those tell us that we're looking at the right numbers. I do also want to give Genentech a lot of credit for very rigorously sharing that data and publishing that data, which helps everybody to design studies that have a greater chance of success.
Yeah. Thank you.
Hi. Phil Nadeau from Cowen and Company. Two questions for the panel. First is on infections. In the Apellis trial, there was a small number of infections in treated patients. I'm curious to get the panel's opinion. Do you think that was mechanistic based or formulation based, as I think the company has suggested? Cedric, can you remind us what you're doing to change the formulation for phase III to minimize the risk of infection?
Yeah. Maybe I'll start with that.
Yeah.
We had in the phase II clinical trial, we were using a lyophilized preparation. In phase III, we will have a filled preparation. That makes a difference in treating the patients, of course. Jeff actually was a very prolific investigator in our clinical trial and went through that process. The problem is that when you take the lyophilized product and you suspend it, there's a lot of manipulation. You have to let it stand for a long while. That will no longer be needed in phase III. To some extent, that is similar with those of you that remember that with Lucentis, which in phase II was also a lyophilized product, and then when it went to phase III, became a liquid suspension. I don't know if you want to add something to that.
Yeah.
There was a higher incidence of inflammatory responses from the phase II study of Lucentis when it was a lyophilized preparation.
Markedly higher.
Yeah.
We remember that.
Yeah.
The follow-up question would be, when we interpret the phase III data, I'm curious to get the panel's opinion when the benefit risk for APL-2 would turn negative, both in terms of the infection rate as well as new onset exudation. Is there any rate of infection or rate of new onset exudation that would give you pause where you'd think maybe a 30% reduction in GA lesion growth wouldn't make up for that risk?
I'll take the exudation if you want to take the infection, Robert.
I think as is often the case in small studies, one or two cases of endophthalmitis make the numbers skewed. I think our overall expectation is that we're going to see rates of endophthalmitis that are going to be comparable to other intravitreal injection studies.
I think as far as the exudation issue, again, I think we'll be very cautious in making sure that the exudation is real. I pointed out that we'll be doing extensive imaging to ensure that. One thing to point out, Jeff showed it very nicely in the phase II trial. This was investigator determined. It was a single mask, meaning the investigator knew the treatment assignment of the patient. There may have been some investigator bias to pull the trigger a little bit earlier. The exudation that was seen in the phase II trial was classified in most cases, in my opinion, as minimal. I don't think the issue is as big as it looks, I don't think we're looking at a percentage.
I think, again, I think simplistically, Robert said it a little while ago, if you're given a choice between an untreatable disease and a whatever % chance of developing a treatable side effect, I don't think that there's a question. I asked you, I asked Robert before we even walked in the room earlier today, if I said you had whatever % chance of getting exuded disease for which I had a treatment but 15 years ago with the vision he had, would there be a second thought about getting the treatment?
No, I'd take the deal.
I don't think there's a number. You take a non-treatable disease, make it treatable, and I have a way to deal with the side effect. I'm good with that.
Yeah. I think it will also depend upon visual acuity. What we saw in these patients that developed exudation.
Yes
There was little to no impact on the visual acuity. Again, we know the ultimate impact of geographic atrophy. If we can control CNV at any rate, that becomes important.
Other questions?
Hi, it's Thara London here with Umer and Regina from Evercore ISI. I suppose we noticed you've included some functional endpoints to the study, and we're wondering, is this a regulatory requirement?
No.
No, it is not. It is more a question of reimbursements. For registration, most regulatory organizations in the world will accept showing that you can reduce the growth of atrophy. For reimbursement, especially in Europe, the functional discussion is important.
Sure. Just to follow up from what you were just speaking about there in terms of neovascularization versus exudation, and just you mentioned more frequent imaging. I suppose, what specifically, or how specifically are you going to assess?
Well-
This comes a little bit down in the weeds, at the end of the day, in order to respect the intent to treat, because we are using an anatomical endpoint, when an image goes missing, and we had images in phase II at zero, two, six, 12, and 18 months. An image can go missing because a patient is on holiday or because an image is blurry and the central readers cannot read it, or the lesion falls outside of the frame. There are many reasons why. You get about 20% attrition or so, if I remember it correctly. To compensate for that, you use an algorithm, which is called a mixed-effect model, which is acceptable to the FDA. What that does is that penalizes you because it essentially takes those values closer to the sham control.
In spite of that penalization, we did meet our primary endpoint. At the same time, when you use more measurements, which in the phase III will be the case for every two months instead of zero, two, six, and 12, if there is an image missing along the way, we get penalized less by this mixed-effect model.
One other point to make is that the quality of the images that will be collected will be far superior because they'll be done to protocol. The range of imaging that will be performed will also be more extensive. For example, systematic acquisition of all the full range of images, including OCT angiography, will allow the reading center to determine in much greater and better detail the pathogenesis of these rather minuscule changes that are happening in the outer retinal interface, if that makes sense.
We'll take one last question. Go ahead.
Hi. Yigal Nochomovitz at Citi. Just three questions, little ones.
Yeah. The last three questions. Yes.
Very easy. Okay.
Sure.
On the endpoint being not the square root, but just the linearized area, does that imply that you need to do something different with respect to stratification of baseline so that you don't have any issues there?
No.
How will that be handled?
No, it is the same. As well as it's properly distributed between the groups.
Okay.
That's it.
When you looked at the lampalizumab data, and this has been presented, it was presented as the rate of progression, but they also showed the square root analysis, and it had no impact on the outcomes. That was almost 2,000 patients.
Okay. With respect to what you described in the images regarding the distinct form of CNV and the classical form, do you have any rough idea just what % of the 20% fell into that more classical presentation?
I don't think you've publicly shown it. You're the CEO of the company. You can say whatever you want about it.
No, we can disclose that. Go ahead, Jason.
I think to keep in mind that from the fluorescein angiographic point of view, a minority of the patients classified as converting to exudative disease in FILLY actually had fluorescein angiographic confirmation of actually having CNV. You're talking about OCT-only confirmation. For those that had fluorescein angiograms, none of them had classic CNV. They were all occult CNV, and the exudation was minimal in a majority of cases. We are truly talking about conversion to exudative disease, and I hate the idea of presenting it as, here are these people with these perfect maculas with just atrophy, and all of a sudden, these neovascular membranes grew out of nowhere. That's not what my impression is.
My impression is that this is exudation, some of which may be RPE dysfunction and not neovascularization, and some of it may be nascent CNV that was present at baseline that became active but couldn't be imaged, it was so fine. That's part of what we'll learn in the Phase III program.
Just one more. Going on Phil's question on the infections. If you do need to treat with both the anti-VEGF and APL-2, how much more concerned would you be on endophthalmitis given that you'd be doubling the number of injections?
I can. We have a number of studies.
Yeah
where we administer multiple injections in the day, and the rate remains extremely low.
Yeah.
Essentially, you re-treat each infection with the full sterile protocol, BETADINE, and everything. That rate remains very low.
There are a lot of clinical trials. You can look at the Regeneron combo. Sorry, the Fovista. Yeah, the Ophthotech program with Fovista.
Fovista was two injections.
Yeah. Fovista was the largest, which was a double injection. Again, we didn't see any significant issue with regard to infection.
In the U.K. sites that enrolled for Fovista, there wasn't a single case of endophthalmitis.
Right. We're not concerned about that.
Usha always likes to tell us the U.K. stuff.
The U.K. They're different than us.
You know why? Because of the protocols that are used over there.
Well, you're just better at it than we are. On that happy U.K., U.S. note. If you have further questions, there's a 10-minute break now.
All these injections.
We will dive deep into paroxysmal nocturnal hemoglobinuria. Thank you.
Attention, attention. All right. Lovely people, break is over. We are now going to move to the second section of the day, the section on Paroxysmal Nocturnal Hemoglobinuria, PNH. The first thing we are going to do is tell you more. Well, I say we, that we for the one and only Dr. Pete Hillmen, who's here with us today. Tell you more about what this disease really is, what it represents, and most importantly, I think this is really something that we take much to heart, is the unmet medical need in patients with PNH. C5 inhibitors do an incredible job for these patients. SOLIRIS is a life-saving therapy. It is something that's truly changed the outlook for these patients.
There is a significant unmet need that we don't think we can address with C5 inhibitors and where we think we have an opportunity with C3 to do something more. PNH for those of you that have met with me on this subject is, on one hand, a proof of concept indication that we can indeed inhibit C3 systemically and hopefully with about 11 patient years behind us now, do it safely, so that we can branch out into other indications. At the same time, it is really important for us to try to do something for these patients that we believe can be helped. Dr. Pete Hillmen requires no introduction in this field.
He came to visit us from Leeds in the U.K. and was the very first person in this world, that at the time went to Alexion and said, "I would very much like to try your C5 inhibitor in my patients with PNH." As such, really has established this incredible standard of care that now is being applied globally. Thank you so much, Pete, for joining us, and the floor is all yours. Thank you.
Thanks, Cedric. Thanks, Cedric, for the introduction and for the invitation to speak at this event, and it's nice to see some familiar faces. It's my pleasure to present Paroxysmal Nocturnal Hemoglobinuria to you and where we are in the treatments and what the unmet need is, and the role potentially of APL-2 or C3 inhibition in this disease. I'm going to talk about two parts really, about to talk about PNH and then to talk about the first treatment-naive patients with eculizumab treated with APL-2. The first part, really the key takeaway is, as Cedric said, eculizumab. We've now been treating patients in Leeds for over 16 years with eculizumab given intravenously every two weeks. We've had patients who have been on that treatment for that long. It's certainly effective at stopping the intravascular hemolysis of this disease.
We know, and I'll show you, that all of our patients on treatment with eculizumab will load their red cells and presumably other blood cells with C3, that leads to extravascular hemolysis, which we didn't recognize in patients prior to who have intravascular hemolysis. This leads to a global reduction in hemoglobin. All patients have a reduced hemoglobin compared to what would be their normal, and a significant proportion continue to require transfusions. In our series, just over a third of patients have required transfusions in the last 12 months. This is the disease PNH. It's the classic triad of symptoms. It's a disease that we see a median age of diagnosis in the early 20s, although we see patients from children up to late age.
It's a disease that when you get this disease, it usually remains with you for the rest of your life or until you die of the disease. It's a disease which has profound symptoms. On the left, you can see the urine of actually the first patient to have eculizumab before he had eculizumab, and this is the classic symptoms that we see with black urine due to the intravascular hemolysis. Really a very frightening symptom for patients when they don't know what the cause of this is, usually clearing through the day, but then often occurring again the following day. What's notable, we've done lots of work looking at the implication of intravascular hemolysis, which leads to the symptoms we see in the disease, difficulty swallowing, severe lethargy. This is lethargy, which really impacts on patients even getting out of bed in the morning.
In a severe case, has a major impact even in patients who aren't anemic. There's an association that about half of the patients develop thrombosis, and this is in critical sites, and I have had the misfortune of managing patients before eculizumab who've basically died with thrombosis in front of our eyes, that we couldn't stop the thrombosis. Then associating with bone marrow failure, which allows the PNH cells to grow, and in fact, these patients effectively replace their whole bone marrow, usually with weak cells that are complement sensitive. The issue for PNH cells is that they're missing some complement regulatory molecules.
We've already seen in the GA part of this afternoon, the role of complement and the early pathway, which converges at C3, where the main amplification of complement occurs, leading to then the activation of C5, which then leads to the membrane attack complex and also the pro-inflammatory molecule, C5a and C3a. PNH cells are deficient in two key regulators of complement. First of all, CD59 or MIRL, which is the main regulator of terminal complement. Therefore, C5 activation leads to terminal complement and intravascular hemolysis. What these cells also miss are DAF, which in fact is just a key regulator of C3. What we didn't know until we blocked C5 was that these patients would accumulate C3 on their red cells, leading to the potential for extravascular hemolysis. This cartoon shows, this summarizes the hemolysis.
What we see in patients who aren't treated with eculizumab or C5 inhibition is intravascular hemolysis. These red cells very abnormally burst in the circulation, releasing hemoglobin, which then leads to symptoms of PNH. When we block that, we get C3 loading, which then leads to extravascular hemolysis with phagocytosis of opsonized red cells, by the RE system. PNH occurs in about 15 patients per million, but in the hematocrit form, about five to six patients per million of the population. Without treatment, has a median survival of around 10 years. For a young group of patients, this obviously has a major impact on their survival. Eculizumab, as Cedric pointed out, has had a major impact on intravascular hemolysis and on thrombosis, but unveils the extravascular hemolysis I'll show you, of course, is not without a significant cost.
If we look at our patients, we have a national service in the U.K., we manage all of the patients really in two or three centers and through our service. We've treated over 300 patients from Leeds with eculizumab for PNH, we can split them into really three groups. Those patients who have a normal hemoglobin, which is the minority, then the rest who are anemic, some of whom are severely anemic, requiring transfusions. What I'll try and convince you is that this isn't really the case. What we see is a spectrum of patients, we're seeing the end of the spectrum who are severely anemic, requiring transfusions. We presented data at the American Society of Hematology meeting in December, where we looked at our database of patients and the patients we currently treat.
We selected out the patients who did not have coexistent bone marrow failure, who did not have low platelets or low neutrophils, and had been on eculizumab for at least a year. That left 141 patients, equally balanced between men and women. You can see the median hemoglobin is low, the normal for a female is 120, and for a man is 130 or 12 or 13, depending on the units. That almost three-quarters were below 120 grams per liter. As I'll show you, the patients have C3 loading, and about a third of patients in the last 12 months have had transfusions. If we look at the transfused patients, in the dark blue are the patients who are regularly transfused, in the light blue are the ones with less transfusions, green without transfusions.
Of course, there's a link to hemoglobin because that's the reason we transfuse patients. Also what we see is the reticulocyte count in these non-aplastic patients is higher than those patients requiring transfusions. They have an attempt to compensate for hemolysis, suggesting hemolysis. As you can see, the C3 loading, particularly in patients who are transfused. If we look at the hemoglobin level, this is the distribution in a normal population. We see obviously a Gaussian distribution, and with a median of 14 to 15 grams per deciliter or 150 grams per liter. If you look at our patients who are not aplastic on eculizumab, you can see there's also a normal distribution, it's just shifted downwards. We have about a four-gram reduction, in the hemoglobin levels of our patients who are on eculizumab.
That leads, of course, to some patients having significant anemia. We see often even patients who are, we think, well controlled on eculizumab having symptoms such as tiredness, but not as profound as when they have the intravascular hemolysis. You look at the reticulocyte count, this is the retics count of normal individuals, so up to 150 times 10 times per liter. In 141 patients with hematocrit PNH on eculizumab, again, we see a shifting up. These patients have a compensated hemolysis with an increased reticulocyte count, sometimes at very high levels. We don't see a reduction in retics in patients on eculizumab.
You look at LDH, which is really the marker of intravascular hemolysis, this is pretty well controlled, although we do have a slightly raised LDH, which is probably related to the extravascular hemolysis, as we'll see as we move on to the APL-2 studies. C3 loading is unusual. It is not actually seen in individuals who are not on eculizumab. This is a patient with PNH who's not requiring eculizumab. You can see this is the red cells. On the x-axis, you can see CD59. These are the PNH cells deficient in CD59, the complement regulator, and these are normal red cells, and there's no cells that are loaded with C3d in our assay here. This is a different patient treated with eculizumab. You can see that there's more PNH red cells because these are being protected.
The normal red cells really have very little C3 loading, but the PNH red cells have a lot of C3 loading. About two-thirds of our patients have this detectable with a direct Coombs test for complement. We look at our group of patients, 141 hemolytic patients. This is what we see. All the patients have loading of C3. This is where normal would be. We don't see any loading. Then you can see that there's a range, but some patients have even over half the red cells with staining of C3 by flow cytometry.
I think, in terms of eculizumab, the key message, as I said before, that we do prevent intravascular hemolysis and thrombosis, but it leads to loading of the red cells with C3, and that leads to a compensated or sometimes a decompensated extravascular hemolysis requiring transfusions in about a third of our patients with indication for eculizumab. This is an obvious target, we've been talking for some time with Apellis about to try and prevent extravascular hemolysis. This is where APL-2 comes. I'm going to present the data from the PADDOCK study, which is a phase II study in patients who are not receiving eculizumab.
The takeaway messages from this are that we see that what is an apparent difference between C3 inhibition is a small number of patients on eculizumab or other C5 inhibitors with better hemoglobin improvements, reductions in reticulocyte counts and bilirubin, which we don't see with C5 inhibition. It seems to be well-tolerated. As I'll show you, the transfusions later on, which are very minimal in this group of patients, and it certainly gives us hope that this approach will be more effective than C5 inhibition. This is the design of the PADDOCK trial, which is the APL-2 monotherapy study in treatment-naive patients, eculizumab-naive patients. These are hemolytic patients, LDH greater than two times the upper limits of normal, with a reasonable size PNH clone, which were over 10% white cells, who were transfused within the last 12 months and were not aplastic, platelets above 30, neutrals above 0.5.
Most of the patients were treated at 270 milligrams daily with subcutaneous APL-2, which is, I've already told you, that eculizumab was given intravenously. It has to be done every two weeks, for treatment duration of two years and beyond. This is the LDH. These are patients who are hemolytic, and you can see that they have a median LDH of 10 times the upper limits of normal, which is what we tend to see in PNH. On the right side of this graph is the Alexion 12-10 data that's been published. This is the long-acting C5 inhibitor. You can see that both have a similar effect in terms of reduction in LDH. There's obviously less patients in the PADDOCK study, 13 in that study.
If you look in more detail at the LDH reductions, what we see, if you look on the right now, the 12 with the 12-10 is what we see with eculizumab. We tend to see patients at the top end of the upper limits of normal, slightly higher. We accept really up to one and a half times the upper limits of normal as being adequately blocked with C5 inhibition. What's promising, I think, about APL-2 is that the levels seem to come down into the normal range. It suggests that we're stopping whatever's causing the LDH rise on C5 inhibition, which is presumably extravascular hemolysis. Also, the hemoglobin increases. This, just for transparency, this excludes one patient who was subsequently found to have metastatic ovarian cancer and was losing blood from a GI tract. Therefore, we couldn't really interpret the hemoglobin.
These are all the other patients in the study. There were two patients who had transfusions. One who was transfused very soon after starting, and a second patient, this chap here, who was not compliant, but when the compliance was improved, responded. You can see that all the patients respond in terms of the hemoglobin of actually all of them. The median, the mean, sorry, is now into the normal range, which we, as I said, we rarely see with eculizumab in PNH. Encouraging in terms of hemoglobin. Mean hemoglobin improvements of three and a half grams. Unusually for C5, we don't see it with C5, is an improvement in both retics and bilirubin, suggesting that the compensated or in some cases decompensated extravascular hemolysis is being stopped relatively quickly.
By one month of treatment, the retic count is down into the normal range, and the bilirubin is down into the normal range. We do see that with eculizumab. I think the early data for single agent APL-2 in hemolytic PNH is very encouraging. We're seeing improvements in hemoglobin into the normal range, which we don't generally see with eculizumab or other C5 inhibitors. We're seeing normalization of the retic count and bilirubin, and we'll see some data for C3 loading. I think these will show in the combination study. It seems to be well-tolerated with the transfusions, which are explicable either early on in the treatment or because the patient wasn't compliant. I think it promises that when we get to the phase III program, we'll hope to see superiority for the whole population of patients in terms of the reduction in hemolysis.
Thanks for your attention.
Thank you so much, Pete, for that presentation. Next, we would like to do what we also did when we talked about geographic atrophy. We have the great pleasure of having with us today, Mr. Barry Katsof. I met Barry last year at the so-called IPIG conference, which is a conference held once a year on the Friday evening before the ASH meeting. He sat with us at our table, and it was extraordinary to hear his life, and he will share some details of that with you today. It also struck a real chord because Barry is an example of a patient that, hopefully, we'll be able to do something more for than is currently the case. Barry, I want to thank you so much for joining us today and sharing your experience with us.
Thank you.
Merci.
When I first got the phone call from Cedric inviting me here, of course, I was very excited to be able to come and share my story with everybody. This is a bit of deja vu for me on a personal level. A company I founded in the early '70s, I did an IPO on Nasdaq in '93, and for 11 years while I was public, I hosted many of these types of events. For me, it's kind of a homecoming in that respect. I'm going to shake up the numbers a bit that I'm going to talk about. I'm not going to talk about EPS and diluted shares, or diluted EPS revenues and GAAP versus non-GAAP. I'm going to talk about blood count numbers, LDH, some of the things that Dr. Hillmen spoke about. Reticulocyte counts, bilirubin, and that sort of thing.
I started my treatments in roughly 2008 on SOLIRIS. My hemoglobin never went above mid-80s. My body got used to living, working at that level, and I kept up pretty much my active life of cycling, hiking, and so on. I was on the standard dosage of 900 milligrams. What we started to see after a number of years was the transfusion need started to escalate. We thought maybe I was getting some breakthrough. In other words, the eculizumab or SOLIRIS wasn't completely blocking the C5. We upped the dosage to 1,200 milligrams every 2 weeks. Same thing, after a year or so, transfusion requirements were pretty much status quo, being every 6 to 8 weeks, I had to go in for a top-up.
We decided, okay, before we go to 1,500 milligrams, let's see if we could do it a little bit more scientifically to see if it is breakthrough or not. We started doing what's called a CH50 test, which we did in the trough or the morning that I was getting my SOLIRIS treatment. After 7 infusions at 1,500 milligrams, it showed that I was fully blocked. I said, "Wow, this is going to be terrific. Cut out the transfusions. I'm now fully blocked and life can go on." I was wrong. After a year at 1,500 milligrams, every 6 to 8 weeks, I had to go in for a top-up. What it turned out to be, as Dr. Hillmen. Excuse me, it's not a cold, it's the air conditioning in here. What Dr. Hillmen was pointing out, extravascular hemolysis.
It was the build-up of the C3, which was causing me to be chronically anemic and which required me to have the transfusions. What's life like with PNH being transfusion-dependent? Aside from every other week. Thank you. Aside from being fixed to a regime of infusions every other week, I have to now start to plan ahead on a 6 to 8-week schedule as to am I going to be out of town? What are my activities going to be? Am I going to need a transfusion? I'm getting much better at it. I don't want to go into the clinic every other day and have my bloods done, I'm starting to understand the signs, what my body is telling me, and I'm trying to go in and get my top-up before my hemoglobin gets below 60. Okay, not much fun.
Getting the transfusions fixes one thing temporarily, causes other things. Your iron or ferritin levels start to go through the roof, so you have to get on iron chelation treatment. Pills every day that reduce the amount of iron in my body. It's not down to normal, but it's down to, I guess, an acceptable level where my doctors aren't overly concerned. The other thing is when you start to get transfusions on a regular basis, you develop antibodies. Don't fully understand what antibodies are, but I know enough to know that I can't go into the blood bank and say I need two units of type A. They have to take my bloods, they have to do a cross-match, and they have to find blood that will match the blood that I have in my system. That's not something that's done in a half hour.
Typically, I'll go in today, have my bloods done, and I'll go back in a day or two to get the transfusion. At times it's a little frightening, I try not to think about it, heaven forbid I should get into a situation where I need a transfusion immediately, and that could be a problem. That's something else that transfusion patients have to live with. I guess in a real world, a perfect world, I'd love to see my LDH always below the upper limits of normal. Right now, because of the extravascular, I'm just slightly above normal. My bilirubin is high, I'd love to see that lower. The reticulocyte count, if I understand it correctly, it's my bone marrow working, running a marathon 7/24 to make blood cells to kind of try and compensate for what's going on in my body.
I told you I have a hemoglobin level on a good day in the mid-80s. I'm active. I still cycle, now I'm on an e-bike, I have to admit. I get a little bit of push going up the hill. I can't imagine what it would be like to have a hemoglobin of 105 or 110. If there's any cyclists in the room, if I get a hemoglobin at that level, you're not going to be able to keep up to me. Of course, no more extravascular hemolysis, it'll cut the need for transfusions and the iron chelation therapy and so on. Going to give you some guidance, and I'm going to hook onto Cedric's forward-looking statements. If I can get my numbers that I just spoke about down into the levels that I would like to, I tell you one thing.
I'm going to hang up that 54 pound e-bike. I'm going to take down my 15 pound full carbon stealth rider, okay? Going to dust it off. I'm going to put on my sexy Lycra shorts. If any of you folks in the room are riders, I will gladly break the wind in front of the peloton. If you guys can keep up, you're welcome to draft behind me. Thank you for listening to my story.
Thank you so much, Barry.
That's all right. Yeah.
Thank you so much, Barry. That is why we try to do what we do. Merci. The next talk, Dr. Anita Hill, the one and only. Anita works with Pete in Leeds, and she heads the group that in the PNH treats all the patients with PNH and has, from what I understand, a bus
Yes
that she doesn't drive. She brings her colleagues, physicians on that bus, and they drive through the U.K. and treat patients with PNH. It's an extraordinary service that, as far as I know, has not been replicated anywhere in the world. It also means that all of these data and this information and this knowledge is centralized in one location. Anita, we're so happy to have you here with us today. Thank you, and we look forward to your presentation.
Thanks very much.
Thank you.
Thank you very much, Cedric, for that introduction. It is a real honor to be here today to present the PHAROAH data, which again, I think you'll see is quite impressive, and we're very excited about the future for our PNH patients. Again, like all the other presentations, these are some of the key takeaways that I'd like you to consider. We'll be focusing on four patients who remain on treatment, and you will see stable hemoglobin levels, which are actually improved from when they were on eculizumab monotherapy, and that these patients have become transfusion independent. The physicians who were treating these patients, therefore reduced the dose of eculizumab if they were on a higher dose before APL-2 therapy, with no change or deterioration in both hemoglobin or LDH.
Not only that, three out of the four patients have been able to successfully stop eculizumab, meaning they are now on APL-2 monotherapy. This combination trial resulted in actually demonstrating that APL-2 could be used as monotherapy. I'll talk more about these patients individually so you have more details. The PHAROAH trial was a trial for patients with PNH who had been on a stable dose of eculizumab for at least three months. They required anemia or transfusion dependency to enter the trial, and again, should have no evidence of underlying bone marrow failure or significant bone marrow failure. We're focusing the presentation on the patients who received 270 milligrams daily. This shows, I think, quite strikingly, that of the six patients who entered the trial, five of them were not managed on the labeled dose of eculizumab.
They were given either 1,200 milligrams every 14 days or even double the dose at 900 milligrams weekly. Only one patient was on the labeled dose at the time of study entry. You can see from this slide that they're anemic. The LDHs are reasonable, so this isn't due to intravascular hemolysis, but the reticulocyte count is also very high, demonstrating significant extravascular hemolysis. Overall, this slide shows that the transfusion dependency, first of all, prior to receiving APL-2 therapy, shown by these blood drops on the left. APL-2 is commenced, and you can see a significant improvement in the hemoglobin and actually a normalization of the LDH for these patients. You can just see three small blood drops here for patients on APL-2 therapy combination, and we'll talk more about these.
One of the patients had the transfusion when she was transiently discontinued from APL-2 for investigation of raised transaminases, and the other two transfusions were required in a patient with a high BMI, where it's thought her dosing of APL-2 was inadequate. I've been told that these two patients have been presented on a previous occasion, so I won't go into them in too much detail. Just to say that the two that were discontinued, patient three, she was morbidly obese and was probably underdosed and therefore discontinued therapy. Patient five was the patient who had a temporary discontinuation to investigate raised transaminases, which were found actually due to biliary obstruction. Stenting resolved those raised transaminases, and she restarted APL-2 successfully. She then became pregnant and obviously had to come out of trial.
Both patients and their doctors have requested that those patients resume taking APL-2. You can see that they must have felt better. There was no other reason for stopping that was an adverse event. That does leave us with four patients who continue to receive daily doses of APL-2 from the original entry. Taking all four patients in total, again, this slide very clearly, and I think strikingly, demonstrates the transfusion requirements prior to commencing APL-2 therapy. The patients then become transfusion independent with a significantly raised hemoglobin and normal LDH. I think this slide is the one to remember. It is very striking. With that, there is also an improvement in reticulocyte count and bilirubin levels.
We can see that this is demonstrated further by the next slide, which shows that those cells that were coated with C3. This slide shows the high levels of C3 coating on the surface of PNH cells at the time here of commencing APL-2. Over the course of approximately the next 12 weeks, those C3-coated red cells are being removed from the circulation or undergoing the natural lifespan of a red cell. After 12 weeks, there are very few C3-coated cells remaining. This spike here is that lady who had the temporary discontinuation. Her reticulocyte count became elevated, so you could consider her as restarting APL-2 at this point. Again, it takes her 12 weeks to clear those C3-loaded cells. With that follows the rise in hemoglobins that have been demonstrated. Let's take the four patients just quickly, but through each one individually.
This is a patient who is on a higher dose of eculizumab than the labeled dose, 1,200 milligrams every other week, and has required a transfusion but is significantly anemic, but with a normal LDH, and this is therefore indicative of extravascular hemolysis. The patient commences APL-2 in combination with their eculizumab, and there is a significant improvement in hemoglobin and the LDH is stable. Therefore, it was decided to reduce the dose of eculizumab to the labeled dose with no change in that significant improvement in hemoglobin or LDH level. Indeed, this patient was able to stop eculizumab therapy. Because of this marginal rise in LDH, the dose of APL-2 was increased to ensure patient safety, and you can see the maintenance of that excellent hemoglobin with continuing normalization of the LDH. On to the next patient. This patient is multiply transfused.
They have had nine transfusion episodes in the 12 months prior to APL-2 at the label dose of eculizumab. This was the only patient on the label dose of eculizumab. You can see, again, LDH is very reasonable, therefore, this is extravascular hemolysis causing this requirement for blood transfusions. This patient commences APL-2, and this is the result. Again, good normalization or improvement in the hemoglobin. Much so that their treating physician actually venosected the patient for the iron overload that you've just heard talked about that can occur in these transfusion-dependent patients on eculizumab. Again, the hemoglobin has improved. LDH is very good. Eculizumab is discontinued with, again, maintenance of that impressive hemoglobin and LDH. The third patient that I'm going to present is on twice the dose of eculizumab, twice the label dose. They're on 900 milligrams every week.
They still require transfusions on this dose, with three transfusions in the year before. Again, LDH is near the upper limit of normal. They commence APL-2, and you can see that impressive rise in hemoglobin without the requirement for any further blood transfusions. That is maintained, and the 900 milligrams of SOLIRIS has gone from weekly to every other week, and you can see a maintenance of the hemoglobin level, as well as the continued normalization of the LDH. Again, the eculizumab was stopped, and the dose of APL-2 was increased at the time of that discontinuation of eculizumab to 360 milligrams every day. The final patient. Again, multiply transfused in the 12 months prior to receiving APL-2, and they again are on twice the label dose at 900 milligrams every week and have required eight transfusions. LDH, again, near normal.
Again, indicative that this transfusion requirement is due to extravascular hemolysis. This, again, is the very impressive and striking rise in the hemoglobin level, and this patient again undergoes venesections for management of their iron overload, which is probably why the hemoglobin remains just below the 12 grams per deciliter. With this patient, and we must remember that this patient is actually one that weighs 125 kilograms and therefore is also obese. When the 900 milligrams is reduced to every other week, they remain stable. An attempt was made at this point to discontinue the eculizumab. This patient had a breakthrough of their intravascular hemolysis, and again, thought to be due to underdosing. The dose was increased to 360 milligrams. With their label dose of eculizumab, again, control is established. There was a second attempt to remove the eculizumab, but unfortunately, another breakthrough hemolysis.
Approval has just been received that we are now allowed to increase the dose for this patient to 440 milligrams. It hasn't yet been done, we just need to see if this is due to underdosing of this, again, patient with a high BMI. That's the summary of the PHAROAH data. You can see that the hemoglobin significantly improves for patients who were previously anemic on eculizumab, and those who are transfusion-dependent have become transfusion-independent when on an adequate dose. Not only did that happen, SOLIRIS was allowed to be reduced and then ultimately stopped in 3 out of the 4 patients. This is why, therefore, we are quite excited about the planned phase III trials.
The phase III trials, which are planned to open in the second half of this year, are designed to look for the improvements that you've just seen demonstrated in the phase II. That we expect to see those improvements because of blocking of both intra and extravascular hemolysis. There should be improvements in hemoglobin, reticulocyte counts, and bilirubin levels, something that we haven't seen in patients on a C5 inhibitor. This is the PEGASUS, which is the phase III trial, which will look at patients who are already on eculizumab therapy. You can see that it's a one-to-one randomization between APL-2 monotherapy and continuing on eculizumab. There is a one-month combination period. The patients who enter the eculizumab arm have the option of transitioning over to APL-2 in the open-label extension period.
Again, patients just require to be anemic for trial entry, and as mentioned, it's a one-to-one randomization. The dose is the equivalent of the 270 milligrams daily or higher dose and will be 1,080 milligrams twice a week through a subcutaneous infusion pump. There is also a eculizumab or treatment-naïve study, which will be held in countries where eculizumab is not available. This will randomize between APL-2 and supportive measures or no drug for 4 months. Patients will have the option to transition over to an open-label extension, which will allow all patients to receive APL-2. This is a two-to-one randomization at the same dosing. I think you can see why we are excited about the opening of these phase III trials to try and demonstrate continuing improvements from what we have seen in patients on current C5 inhibitor therapies.
Finally, to summarize, we have seen significant and very clinically meaningful improvements in hemoglobin level. Only 1 out of the 20 patients who was on an adequate dose of APL-2 required a transfusion. Again, that 1 patient was likely due to underdosing. That we are able not only to add APL-2 and show improvements, but that it can actually also be used as monotherapy with superior hematology. It has been well-tolerated to date. Thank you very much for your attention.
Thank you so much, Anita. We are going to have a small session for questions and answers. Please, Anita, and then Barry, if you wouldn't mind joining us as well. Okay, wonderful. Thank you so much. Well, I think in the interest of time, I think we should just ask the audience what their questions are because they'll be far more interesting than what I have to say. We have the same process with microphones. Yes, please.
Justin Kim, Cantor Fitzgerald. We've heard a growing body of evidence bring to light the unmet need associated with extravascular hemolysis, as measured by reticulocyte counts, bilirubin, transfusion dependence, and even C3 loading. Is there any available evidence or even a theoretical hypothesis to believe that novel C5 inhibitors would be able to address these areas of unmet need in the SOLIRIS-treated populations?
No, I think it's probably fair to say that the C3 loading and the extravascular hemolysis is a class effect of C5 inhibition. If you block C5, you then allow the upstream loading of C3 and PNH red cells, because they're missing the principal C3 regulatory molecule, DAF, are unable to deal with that and therefore load up. I think we're seeing it in vitro and slowly in vivo now. The same effect will happen with any C5 inhibitor, I think.
Yeah, I agree.
Maybe touching upon the ability to wean eculizumab and convert combination-treated patients to APL-2 monotherapy has been very interesting. If APL-2 were commercially available, what are the considerations you would make as a treating physician to maybe initiate such a switch?
Yeah. If obviously it was commercially available, that would assume that the phase III trials have been successful and most importantly, that there have been no safety concerns for us to proceed. In that case, it's going to be a very interesting time because we then will have a drug that, unlike C5 inhibitors, will actually block both the intra and extravascular hemolysis. With those caveats in place where safety has not been a concern, I think it would be hard not to be switching patients. Obviously, price will also be an issue which we will talk to Cedric about at some point. There would be a very strong argument for switching all patients to combat both elements of the disease. Would you say?
Yeah, I think also that it's fair to say that the patients that Anita presented in the first study were the most severely affected with extravascular hemolysis because they were transfusion-dependent, had high doses of eculizumab. We have many patients who are anemic and have some symptoms. I think what we can expect to see is the hemoglobin normal distribution moving up towards normal. We know from multiple studies in other disease areas, other therapies like erythropoietin, for example, from cyclists who use it in the Tour de France. That an increase in two grams of hemoglobin is really significant in terms of patients' functionality, really. I think it's very attractive.
Thank you.
Hi, Regina Grebla from Evercore ISI. In your last update of the LDH data for PADDOCK, we saw a week 8 multiple of 0.6 times upper limit of normal. In today's update of that chart, the multiples going out to week 16 are closer to one. Can you give us any color about the patients with a longer follow-up? Did their LDH levels increase over time, or are these values being driven by a patient with an LDH above one?
Yeah. We don't know why, but in the first month, we see a real aberrant correction in LDH that takes place, and then afterwards, a little bit. We don't have a full explanation for that, but it may have to do with the fact also that there are more red blood cells in circulation that would be a source for LDH. I don't know, Pete, if you want to-
I think we would expect to see an increase in PNH cells because we don't have transfusions and we don't have the hemolysis. The likelihood is that you'd see more LDH for that reason. Also, I guess, I've not seen all the data in all the individual patients, but you've got a relatively small number of patients out at that far time point, look at four. Obviously, there's a much bigger range. I suspect that might have a part to play.
Madhu.
Hi, Madhu Kumar from B. Riley FBR. First question is about how do you think about the pharmacodynamics of the hemoglobin restoration versus the C3 reductions that you see in the study, and how those line up, and how you think about how the drug works on the mechanism.
When the patients are on the C5 inhibitor, their red cells, as Peter explained, are loaded with C3 and so are being removed by the reticuloendothelial system. Very much by the fact that when you commence a C3 inhibitor, that those C3-loaded cells, those will slowly be eliminated from the system due to the natural history of the red cell itself. Because there is no further extravascular hemolysis, that's why there's already been a drive, as shown by the high reticulocyte count for the bone marrow, to produce red blood cells. Those red blood cells are not being removed, that's why you get such a dramatic increase in hemoglobin at that point.
How do you think about the pharmacodynamics of the subQ APL-2 versus eculizumab and how it might affect the time to transfusion that you see in the patients who do have to transfuse after APL-2 in the treatment-naive study versus the kind of studies you all did before with Soliris in larger trials?
Well, in the Soliris trials, it took six months for all the patients to require a transfusion in the placebo arm.
The median.
For the median time. Yeah. Trying to predict what will happen with APL-2.
I think what you can say is that the transfusions, to both your questions, that of course, these patients are on transfusions before they start. The improvements in hemoglobin is not just the survival of the PNH cells, it's the removal of transfusions as well. It's more profound than just the improvements in the PNH cells. The change in the speed at which the retic count goes down and the in vitro, we did some work with APL-1 and APL-2 looking at the loading of C3. We don't see C3 loading on cells. I think that starts straight away, and we probably will see a quicker response. Within a month, the retic count is normal, which suggests that the extravascular drive has reduced significantly because otherwise you would have a retic count. I think the other point that Barry made, I think, is regarding iron chelation.
One of the things we've seen with Soliris treatment is the increase in ferritin, and it's something which we worry about. We have a history of venesection patients. We know the chelators are difficult in some ways with toxicity or inconvenience. We do remove blood every two to four weeks off patients, and that's probably why some of the patients are a little bit anemic. I'm interested in Barry's thoughts because it's always a bit odd for patients who've been transfused for years and years and years, and now they're giving blood back.
What's that do to the hemoglobin level?
Yeah. Well, the hemoglobin.
Yeah
12, we're happy to venesect people then.
Oh, okay. 12.
That's the most efficient way of getting iron out of somebody, as the most efficient way of putting iron into people is to transfuse them.
It can then keep you chronically slightly anemic if we're doing it regularly.
I'm already there.
I know.
Looking forward, how do you think about strategies for strictly maintaining patient compliance? Because it's very clear from this data that missing even a few doses can pretty dramatically affect a lot of these blood biomarkers. How do you look at ensuring patient compliance, particularly to phase III and more of the long-term if this were to be adopted?
I can. We've actually thought quite a lot about that, obviously. With the PK/PD of APL-2, we could do once-a-week subcutaneous injections or infusions. We would be playing close for comfort. That's actually precisely why we decided to do twice-a-week dosing. To make sure that if a patient forgets, we have that five-day or so window to make up for it. Now, we are working on a drug device combo. With a drug device combo, should it be successful, there will be cloud communication where we will actually know that the dose was taken on the right day. Should it not be taken, we can remind the patients, and after a few days, even take more drastic measures to make sure that we don't end up in that situation.
Just to talk about eculizumab, because we give over 6,000 infusions a year to our patients on SOLIRIS. We may have missed one patient who's not had a dose, who didn't tell us about it. If we look at the patients, we have one or two patients nowadays, because originally we had patients who had PNH for years and were very symptomatic and really felt the benefits of SOLIRIS because they'd been transfused for a long time and very symptomatic. Now we're taking patients very early and starting the treatment, so they're dealing with the diagnosis of PNH and then they're on treatment, and then they don't really remember what it's like. We've had one or two patients recently who wanted to stop, and within two or three weeks they want to go back on.
I think you'll find that if someone isn't very compliant, it won't be long before they become more compliant. Is that fair?
Yeah. It's definitely fair. What I say is if a patient misses a dose and has a breakthrough, they'll never miss a dose again because of how they'll feel, and also unfortunately, because we have seen it, you can have a significant thrombotic event at the time of that breakthrough.
Thank you. We will take one last question if there is one. Yes, Jason, please.
I guess just one quick question. Now we have a longer-acting C5 inhibitor, it seems that ALXN1210 is behaving a little bit better than eculizumab. I guess I just want to get your view, how would you compare the profile of APL-2 versus longer-acting C5 inhibitor? Does it do the same thing on hemoglobin, reticulocytes, and the other parameters that we should look at? Thank you.
Firstly, as Pete has already explained, with ALXN1210 being another C5 inhibitor, it will have no additional benefit on the extravascular hemolysis. Therefore hemoglobins will remain the same as on eculizumab, as will the reticulocyte count, as will the bilirubin level. I do understand that some of the data seem to favor ALXN1210, we also have to remember that those patients on eculizumab were only on the label dose, there was no adjustment for that dosing in the eculizumab arm. What would be good to compare is if you remove those patients where it looks like the eculizumab dose wasn't adequate in the trial, then you'd probably find that ALXN1210 is equivalent to eculizumab rather than showing any major favoring in one direction or not. Yeah, it's again, ALXN1210 is similar to eculizumab. It just has the longer acting.
I would ask the patient, which would they choose? Would they choose an eight weekly eculizumab essentially, or a drug where from the data you've seen today, and if it's borne out in phase III. I'll ask you that question, Barry.
I would probably go with the 1210 only because of the frequency of having to not go in for an infusion every two weeks.
Yeah. That's compared to eculizumab?
Yes.
Then if you have the choice of 1210 or APL-2, knowing that at the moment we only have the data to date, what would your answer be?
APL-2.
I think I'll just add a couple of things. First of all, I'm still with Alexion, I know they had talked to me at the last meeting precisely by saying, "I hope you hold all the other companies to the same degree of stringency." They've only transferred patients who are well-controlled on 900. We have an issue on the patients who are on high doses, because we definitely have about 20% of patients who need a higher dose. It may well be that 1210 is adequate for the dose they're using, but we just don't have that information yet. I think it's important that's out there. I think the key question in terms of comparison, assuming both the drugs go forward, is the comparison whether the results we're seeing with APL-2, we see those increases in hemoglobin across the board.
I think we probably will see them. I think it just comes down to safety, personally. So far we're comfortable with that. If we've got a drug which increases the average hemoglobin to above 12 or 13 grams compared to one that we know is about 10, I suspect that the former drug will be better, and that's what APL-2 looks like it might do. At the moment, we've got a lot of experience with C5 inhibition. We're comfortable about how to manage that modality of treatment to stop thrombosis. We know about infections, we're comfortable with it. There are some patients, many patients who will have an unmet need.
At the moment we may, maybe a third of patients would say, "Okay, I'm too anemic or transfused, and therefore I'll go for APL-2." If the results are as we hope they'll be, it may well be a game changer in terms of complement inhibition.
Thank you so much. It's worth mentioning that a couple of years ago when Pete and Anita told us about this disease, we already recognized SOLIRIS is a life-saving drug, right? It's an incredible product that's made so much difference for patients. Rather than telling patients to stop taking SOLIRIS or ALXN1210 and try something new, which you or most patients probably would not want to go through, we said, let's take advantage of the fact that C3 encompasses C5. What we would like to do is have a scenario, which is why we designed the phase III the way we did, where patients for one month can take the C3 inhibitor. You could take APL-2 and try it for one month, and if it doesn't do anything for you, that's okay, and you're still on ALXN1210 or on SOLIRIS.
If you feel better, you can make a choice with your physician as to whether it makes a difference or not. That's what we would like to do in this condition. That is the end of our panel discussion. Thank you so much.
Thank you so much.
Thank you so much, Pete.
No worries.
My chair has been taken away. Thank you. Sorry. We are moving towards the last section of the day. We have, as I mentioned earlier, the great pleasure of having Dr. Dick Glassock here with us to discuss anything related to the complement-dependent nephropathies. And obviously, Pete and Anita can answer any questions on the autoimmune hemolytic anemias as well. Let me briefly show you what we have going on in early clinical development with APL-2. First of all, on the autoimmune hemolytic anemias. What you see there is a pie chart that shows you the overall AIHA population with about 20%-25% of patients falling in the so-called cold agglutinin disease category, 60%-70% falling in the warm antibody autoimmune hemolytic category, and 5%-10% a mix between the two.
I would like you to remember that, because later on that becomes relevant as well. The key difference between cold agglutinin disease and warm antibody autoimmune hemolytic anemia is that cold agglutinin disease is characterized by IgMs directed against proteins on the cell surface, whereas warm antibody autoimmune hemolytic anemia is characterized by IgGs. That is an important difference because with IgMs binding themselves to the cell surface, we will primarily cause extravascular hemolysis through C3d deposition. When we are talking about IgGs, there is a dual mechanism that will contribute to extravascular hemolysis. On one hand, C3d deposition, but on the other hand, interaction with the Fc gamma receptor on the macrophages in the liver and the spleen.
Therefore, where we stand today, and based on the knowledge around the mechanism, what the drug does, the proven pharmacology of APL-2, we can expect APL-2 in cold agglutinin disease to hopefully show beneficial results. In the warm antibody population, it will be interesting to see how C3d deposition on red blood cells correlates with pharmacology. This is warm antibody autoimmune hemolytic anemia. What's typical about this is that these IgGs will bind to these cell surface proteins, regardless of the temperature. In other words, at room temperature, this binding will take place, and as I mentioned before, the extravascular hemolysis will take place through the deposition of C3b transferring into C3d, but also the interaction of the Fc component on those antibodies. Dual mechanism at work.
In cold agglutinin disease, we are dealing with IgM molecules, which as you can see there, consists of five IgG-like antibodies linked together. Those are stronger activators of complement than normal IgGs. They also are characteristic in the sense that they will only bind to their target under these cold circumstances with temperatures typically believed to have to be below 30 degrees Celsius. That means that the attachment of these antibodies to the red blood cells will typically take place in the extremities when the blood circulates through the blood vessels there. When the blood then recirculates, these antibodies can come loose again, but the damage has been done. When these antibodies bind, complement gets activated, C3d gets activated, and as you may remember, once it is there irreversibly bound, the end product, C3d, is there to stay.
When these red blood cells, like in PNH, reach their threshold of accumulation, they will be removed in the liver and the spleen. The unmet need in warm antibody autoimmune hemolytic anemia, about 15%-30% of patients are non-responders to corticosteroids. With splenectomy, about a third of patients still encounter relapses, in spite of, needless to say, splenectomy being a dramatic intervention. With cold agglutinin disease, steroids and splenectomy are generally not that effective, about 10%-14%. Rituximab does have a response in about 50% on average, but there you have a median duration of remission of approximately only 11 months. The safety elements associated with these interventions, so the current standard of care, of course, also leave much to be desired for.
We decided to start a phase II clinical trial in autoimmune hemolytic anemia, to evaluate whether APL-2 can improve the conditions in these patients. It is primarily obviously driven towards the evaluation of safety, but the secondary endpoints include hemoglobin, red blood cell transfusions, reticulocytes, LDH, haptoglobin, bilirubin, and also FACIT and LASA quality of life scores, very similar to what you would do in a PNH study. We want to enroll 12 patients in total, 6 in the warm antibody autoimmune hemolytic anemia category, and 6 in the cold agglutinin disease category. Those 6 are split between 2 70 milligrams, which we know to be an efficacious dose in PNH, and 3 60 milligrams, between those two pharmacological doses, having a sense of a dose response as well. Key inclusion criteria. We were very broad with our inclusion and exclusion criteria.
Patients above 18 years, below 125 kilograms, must have a primary diagnosis defined by the presence of hemolytic anemia and positive DAT for a warm antibody or cold agglutinin disease, hemoglobin levels below 11. Again, broad criteria for this proof of concept. Specific for warm antibody autoimmune hemolytic anemia, we wanted to enroll patients that had relapsed from or did not respond to at least one prior alternative therapy. Exclusion criteria, without going through all of the details there, it is important to point out that these autoimmune hemolytic anemias are often secondary to other conditions, including neoplasias, et cetera, and that is just to make sure that we have a relatively clean population to evaluate. Here are the data on our first 2 patients treated with cold agglutinin disease. The enrollment there, we had relied a little bit too heavily on one site.
We have broadened that now. We expect to have much more data in the months to come, but this is your first flavor on what we saw with APL-2 in cold agglutinin disease. The first patient here, which was dosed with 2 70 milligrams per day, unfortunately, has difficult blood to handle. Patients with cold agglutinin disease, when you take a blood sample, tends to agglutinate. We have a few missing data points, but the trend looks promising. This patient had a baseline hemoglobin of 10, is now at about 11.5. The reticulocytes also are trending in the right direction. A second patient, which, as you can tell on baseline, had a hemoglobin level of 8, and this patient has now a hemoglobin level around 13 and a half.
The evaluation of the treating physician was, he called this N of 1, with all the caution that that entails, an exceptional response. I think it's too early to tell that, but we are very encouraged, again, based on the fact that we know how this drug works. With the expectation that it should have an effect like this. As you can tell here, the reticulocyte correction as well looks very promising. As we get more patients enrolled in our cold agglutinin disease cohort, we're optimistic that we'll be able to repeat what we saw here based on, again, the mechanism of APL-2. Here is what we have in the warm antibody, the 2 patients with warm antibody AIHA that we treated.
I'm going to start with the orange patient here, which clearly, both based on hemoglobin levels and reticulocytosis in this case, is not looking like a responder. I think it is, even with these limited data, that is quite clear. We are doing the analysis to find out how this correlates with C3d deposition. Is this related to the fact that there is the Fc gamma component that is playing interference? We will find that out. As we get more patients, we'll be able to get more clarity on that. The second patient, which you can see here, is a patient that looks quite promising, going from seven to nine and a half grams per deciliter in hemoglobin, with a reticulocytosis also reflective of clearly the bone marrow becoming more quiet.
With caution, these are the very first patients, but we wanted to share with you what we have so far. Again, in the months ahead, hopefully we'll be able to replicate some of these data. Our analysis right now is that in cold agglutinin disease, we are optimistic. In warm antibody autoimmune hemolytic anemia, we may have to do stratification, and we see where we end up. It is also possible that this patient, which is clearly quite a dramatic early potential response, could be related to the fact that this may be one of those mixed patients, where the cold agglutinin piece plays a role. We will determine that again in further studies. Moving on in the complement-dependent nephropathies. Here we really decided to do a study looking at 4 types of nephropathies in a broad discovery of what APL-2 could do.
You've seen this slide many times before, but the key here is, again, APL-2 acting centrally, affecting all of the downstream effects, regardless of the source of complement activation. Here, I apologize, this is a little bit of a busy slide. Very busy slide. The 4 types of nephropathies are outlined there: IgA nephropathy, membranous nephropathy, lupus nephritis, and C3 glomerulopathy. As you can tell, the different complement pathways of activation can play different roles in each of these conditions, which is why with a C3 inhibitor, we thought it was a great way to explore what can be done. You can see the difference in prevalence and incidence between these four, as well as the rate at which these patients progress to end-stage renal disease.
In the competition, which there is quite a bit of competition, but especially in diseases like lupus nephritis, C3 glomerulopathy, as well as in the others, we believe that we provide a unique mechanism of action. We have some promising data with a mass inhibitor that was tested in IgA nephropathy with promising early results. We will see what that does with C3 inhibition. C3 glomerulopathy, as the name indicates, at least by mechanism, should be a disease where APL-2 hopefully will have a beneficial impact, and as well as in lupus nephritis and membranous. The study design, again, it is really a discovery phase for us. We are entering into nephrology, but it is one where we are focused for now on showing a reduction in proteinuria.
That is a relatively easy way to measure initial pharmacology in a single arm, single open label with APL-2 still being given in daily dosing. It will be up to 48 patients, 6 to 12 in each of the 4 different types of nephropathies. The inclusion criteria, again, quite broad. This is exploratory. Without going into too much detail, what I think is important here is that these patients need to have stable blood pressure, eGFRs above 30 milliliters per minute per 1.73 square meters, a prior diagnosis that was made by renal biopsy so that we know exactly what is going on, and then some of the other important inclusion criteria, as well as the baseline, which is a urinary protein to creatinine ratio above 750 milligrams per gram.
Key exclusion criteria, use of these alternative medications in the six months prior to screening, because that would confound the data. Previous treatment with APL-2, which right now is, of course, not an issue. History of organ transplant, current unstable kidney function for other reasons than the pathology that we're actually investigating. Here we come to the end of our afternoon. You're still all here. We're very happy to see that. In conclusion, where we currently are, we showed you the data earlier this year on geographic atrophy, the 18-month safety, the phase I-B monotherapy expansion. We now have the weaning in the add-on study, and very early, I don't want to call this yet a proof of concept, but a sliver of hope in the autoimmune hemolytic anemias.
What I would like to do in closing is to most importantly thank again our guests that have come here with us. Actually, before I do that, are there any questions on the complement-dependent nephropathies and on the autoimmune hemolytic anemias? No. There will be much more to be shared in the months ahead. At this point, I would like to thank the people who have joined here. Maybe if you wouldn't mind standing up briefly so that we can give you a well-deserved round of applause. Thank you. You too. Thank you so much. Then we have Oh, your boxes. This is the moment. Sorry, I was a little bit confused. We have one more thing for you. When you arrived here, you all received this gigantic box, which we had specifically measured so it would fit under your chair.
You now all have permission to open your box and look what is inside of it. I feel like Santa Claus. These are derby hats. I know you're all wondering what the hell is going on. What do derby hats have to do with an R&D day? Take your time. You're welcome to all wear them. You all look great, let me tell you. The reason why we gave you all these derby hats is because, as you probably know, Apellis Pharmaceuticals was born and raised, no pun intended, in Louisville, Kentucky, the home of the Kentucky Derby. Thank you so much, Tim. The home of the Kentucky Derby, and we're very proud of that, actually. It's a special place, and it's a unique situation to be in as a biotechnology company.
The other aspect of this is that we like to think of drug development as a horse race. In a horse race, you have the finish line, and that's very exciting when it's the end of the race and you arrive and you know which horse has won. Really, the road towards getting there, in my opinion, is as exciting and maybe even more exciting because you live through these days of hope, you live through disappointments. There are so many failures. It takes so long. It costs so much money. It is hard. Even though the right place to celebrate is at the finish line, as we go through this process, we like to, once in a while, sit down and enjoy the moment.
This is one of these moments because, as is rather unusual in biotechnology, we were fortunate, thanks to the great work our executive vice presidents of all of our clinical work, Federico Grossi. Why don't you stand up, Fede? Let's all give him a round of applause here. Because Dr. Grossi and his team were actually able to enroll the first patient in our phase III clinical trial in PNH ahead of schedule. To celebrate that special moment, we thought we would take you on a special ride through a real-life vision of the Kentucky Derby. Here you go.
Who are now 10 off, will have gone to the next major race.
Autoimmune disease, one of the most important medical races of our time. No effort to overcome this challenge is more storied than the race to fight PNH. SOLIRIS has led the race since 2007, but no team shows more promise, more vision, more get-go than the fabled stables of Apellis Pharm. In 2012, Apellis Pharm's Pascal Deschatelets gave birth to APL-2. She was strong-willed, versatile, fast. In a phase I study, APL-2 was bound to inhibit hemolytic activity. Now Apellis plans to put her to the test. We have now the very first patient in a phase III trial with APL-2.
Announcing our phase III clinical trial.
We have now recruited the very first patient in a phase III trial with APL-2.
At the start is SOLIRIS, running in a seven-patient enrollment trial. For the first period of one month, these seven patients will receive both SOLIRIS and APL-2 during this period. After one month passes, the seven patients will be broken into two groups running on parallel tracks. On track one, 35 will be turned to taking only SOLIRIS. On track two, 35 will receive only APL-2. 35 on one side, 35 on the other, during this trial of four month period. All eyes on these remarkable numbers. We will see if APL-2 will perform better than SOLIRIS. This could be a legend in the making. Good luck to Apellis Pharmaceuticals, researchers, physicians, and patients who will benefit from the making of APL-2.
Put on your hats and join us for some rare research into the next move. Celebrate the development of APL-2.
Thank you very much. We're very happy. We thought we'd make it a little bit cute. We obviously take this all very seriously, but we thought that at the end of this day, you've been able to sit through all of this. We wanted to thank you, not just with this little video, but we've also prepared a special drink, the mint juleps associated with the Kentucky Derby, which I invite you to indulge in with moderation or not in the next hour, and we look very much forward to talking more in the next couple of hours. Thank you so much for coming, and have a wonderful evening. Let me add one more thing after this. It's completely confused. We do have to thank one person in particular, Alex. Where is he? There he is. Alex from our investor relations firm, W2O. That's a commercial for you.
Did an amazing job helping us putting all of this together. You've been incredible. Thank you so much