Cognition Therapeutics, Inc. (CGTX) Earnings Call Transcript & Summary

Good morning, everybody. Thank you for joining us on our age-related macular degeneration symposium today. My name is Lisa Ricciardi. I'm the President and CEO of Cognition Therapeutics. And on behalf of our team and our advisers, I welcome you to this discussion. Today, we'll be reviewing our data presented at ARVO last month. We'll also be reviewing our rationale for why we are choosing to advance in the dry age-related macular degeneration. All of this will be discussed against the backdrop of current therapies and new insights relative to age-related macular degeneration. Please note, as a public company, we'd like to point you to our forward-looking statements. You're welcome to review this on our website as well. I apologize, there is a delay in advancing the slides. So let me turn briefly to who is Cognition Therapeutics. As many of you know, this is a company that started as a research-based [ MC ] in Pittsburgh a number of years ago. The company was founded based on the scientific founders' interest in learning and memory and synaptic function. Today, many years later, our areas of focus are age-related degenerative disorders of the CNS and of the retina. Now let's translate that into disease and what we're talking about is Alzheimer's disease, dementia with Lewy bodies, Parkinson's disease and age-related macular degeneration. Our scientific and clinical studies have focused on the sigma-2 receptor complex, and our lead program in dry AMD indeed targets this receptor. Notably, we have received over $160 million of funding. This covers much of our Phase II programs. And of that money, we have $100 million in funding left to continue to progress our clinical studies. In addition, we are the happy recipients of two Michael J. Fox Foundation awards, which are being used to look at new models for Parkinson's disease. Key data readouts for the company will be coming over the next 12 to 24 months with our first readout anticipated for the end of 2023. This will be from our SHINE study in mild to moderate Alzheimer's disease. Now looking at our pipeline, let's cover this in brief. We have multiple Phase II programs. Our SEQUEL program is nearing completion. Two studies are actively enrolling patients, our SHINE study in mild to moderate patients as well as our study in dementia with Lewy bodies. I would note that our DLB study has received the largest grant ever granted, awarded for this condition, a $30 million grant. In addition, at the end of this year or in the second half of this year, we intend to be enrolling patients in 2 more studies, our study of early patients with Alzheimer's disease done in collaboration with our partners, the ACTC; and then importantly for today's discussion, our study in patients with dry AMD. Now you have already heard me talk a lot about our work with Alzheimer's disease and other dementias, and yet here we are embarking on a significant trial in dry age-related macular degeneration. In our panel today, what you will learn is how the Sigma-2 receptor impacts both trafficking, neuronal trafficking in the brain and the eye, and how it impacts autophagy, two areas which play a meaningful role in this disease state. I'd like to briefly introduce our speakers. We are so pleased to be joined by Dr. Karl Csaky. Karl is Chief Medical Officer of the Retina Foundation of the Southwest based in Dallas. He's the T. Boone Pickens Director of Clinical Innovation for AMD. Karl has extensive involvement with clinical trials in retinal diseases and has developed a number functional assessments. In addition, if any of you are members of the Macula Society, the Retina Society, AAO, ARVO or ASRS, you may have seen him strolling the halls of those meetings. We are delighted to be joined by Dr. Jennifer Lim. Jenny is a Director of the Retina Service at the University of Chicago, University of Illinois in Chicago. Jenny has a very extensive practice performing retinal surgery. She has a full teaching load and, like Karl, has extensive experience doing clinical research. She has a very active practice. We're very pleased to be joined this morning by Jenny. Coming from the U.K., Dr. Arjuna Ratnayaka. He's Associate Professor and researcher at the University of Southampton, as I said, in the U.K. Arjuna has done a number of [ more exciting ] retinal disease tissues in the aging population. He's done a variety of -- worked with a variety of models, including donor tissue models, and he has been an important collaborator for us. In fact, the work you'll see today was done in conjunction with Arjuna. And Dr. Stella Robertson. Stella has extensive background in ophthalmology research at Alcon. And after which, she formed a consulting practice, Arrochar Consulting, where she advises a number of small companies. Lucky us, we're one of them. Stella was a Co-Founder of Bios, which is Texas-based private equity firm. She's been very involved with Cowtown Angels. Stella's career has really been around innovating small and large companies to work in this space. We're pleased by all of them. Now let's briefly talk about our agenda. Tony will begin explaining our clinical thesis, why is it we're embarking this path. We know that this is a tough area. Karl will then take us through aspects of dry AMD with a particular sensitivity to the patient burden in this disease as it progresses. Dr. Mary Hamby will review our ARVO data. By the way, that poster is on our website, in our publications and in our Events page. And then from here, we'll move into a panel discussion with all of our colleagues. Now I'm going to turn this over to Dr. Tony Caggiano to lead us off. Tony is our Chief Medical Officer and Head of R&D here at Cognition. He's a MD-PhD from the Pritzker School of Medicine at the University of Chicago. Tony's background brings extensive drug development experience at Acorda and at a whole series of innovator companies. He is responsible for all of our fleet preclinical work, our clinical work and our medical operations. So with pleasure, I say, Tony, over to you.

Thanks, Lisa. So for those of you who might not be extremely familiar with Cognition, I'm going to give you a little history of our background. So the company was founded by a chemist and a neuroscientist. The chemist was -- had a very unique library with properties that we felt had promise for developing CNS active drugs, and our neuroscientist had keen interest in the toxicities of A beta oligomers and their role in Alzheimer's disease. They had a phenotypic screen looking for molecules from within this library that could protect neurons from the toxicities of these A beta oligomers. We found early on that our hits were all ligands for the sigma-2 receptor, so this became the de facto target for the company. Now Cognition is a clinical-stage company developing therapies for diseases of the CNS and retina. We have labs in Pittsburgh, Pennsylvania and our headquarters is in Purchase, New York. Our lead molecule is CT1812. This is an orally delivered small molecule selective ligand for the sigma-2 receptor and has good access to the brain and retina. And as you'll see and as Lisa mentioned, we are now in multiple trials in Alzheimer's disease as well as in dementia with Lewy bodies. So the company started around a membrane trafficking [ stream ]. So our scientists have identified that when neuron were exposed to the A beta oligomer toxins, the movement of vesicles or membrane trafficking within these neurons was disruptive. And so this was used as the [ stream ], the select molecules from the library that had properties to be able to restore the normal trafficking within these neurons. And as I mentioned, our [ hit ] chemistry, we identified and patented 5 unique chemical series and [indiscernible] CT1812 as well as a number of [indiscernible] 12. So membrane trafficking with a movement of vesicles is one of many key cellular homeostatic processes that occur in all cells, and it's the process by which things that are produced with the Golgi are distributing throughout the cell as well as how the cells take up waste and bring it back to recycling. In degenerative conditions, whether in the CNS or in the eye, this process is largely disrupted, leading to cell death and dysfunction. And what you'll see here, and what we'll tell you about is how our sigma-2 ligands and our critical lead, CT1812, further activity at the core proteins within the sigma-2 receptor, PGRMC1 and TMEM97. [indiscernible] So membrane traffic is very important in the brain and in the eye. So in the brain, membrane trafficking or movement of vesicles is important for moving proteins, nutrients, transmitters from the cell body out to the periphery as well as taking waste and moving it back for recycling in the brain, in the spinal cord, in the neurons. Sometimes this process has to occur over up to a meter as things are transported from the spinal cord all the way out to, say, the feet. Disruption of this process in neurons is one key component of neurodegenerative conditions. In the eye, membrane trafficking or movement of vesicles is particularly important within the supportive retinal pigmented epithelium. So the RPE is responsible for moving to grading and recycling the used or spent photoreceptor outer segments from the [indiscernible] and [indiscernible]. Disruption of this process is a key component of dry AMD. So our approach now is to use our modulators of sigma-2, specifically our clinical CT1812, to modulate these processes to hopefully improve both neurodegenerative and the conditions of the eye such as dry AMD. We know that the sigma-2 receptor is widely expressed in both the retina and the brain. And what we know from the literature and what we'll show you today is such as autophagy, cell survival, trafficking and cell function with our sigma-2 ligands, specifically CT1812. So this process is particularly relevant in dry AMD. So as we mentioned, the disruption of movement and recycling of photoreceptor outer segments is a key pathophysiologic hallmark of dry AMD. So when the RPE are exposed to toxins such as A- beta oligomer or protein aggregates or oxidative stress, the protein receptor outer segments build up. Not only do they build up, but one nice feature of this is that we can visualize this buildup of segments and proteins through the process of Autofluorescence, which makes a key and convenient way to both track disease as well as potentially monitor changes caused by therapeutic interventions. So our approach to treating dry AMD is to use our sigma-2 modulators to protect the function of RPEs. By protecting the function of RPEs, we believe we may be able to protect the retina and slow the progression of geographic atrophy. Now as you'll hear from Mary and the others, we did not arrive at dry AMD simply by chance. We used analysis of biomarkers from our clinical samples in Alzheimer's patients to identify that dry AMD is a promising pathway. Genome-wide association studies confirm this. We observed key bits of evidence from the literature. Looking at knockdown of the sigma-2 protein means we can affect the function of RPEs with CT1812 and our other sigma-2 ligands. So what you'll hear as well is that we will be leveraging the safety data that we've accumulated through our Phase II program in Alzheimer's disease to go directly into this proof-of-concept study following clearance with the FDA. So this will be a study we have approximately 100 patients per pool treated either with CT1812 or placebo once daily and followed for a year, with the primary outcome being change in geographic atrophy. So now we're going to turn to some recordings, presentations that we did at ARVO earlier this year. So first up will be Dr. Karl Csaky, who will be telling us about the disease state, the patient experience and how researchers and ophthalmologists are trying to intervene in dry age-related macular degeneration. [Operator Instructions]. Thank you.

So I'm going to talk today a little bit about age-related macular degeneration, review of the disease, patient burden and the industry landscape. So, as we know, macular degeneration or AMD is really a multifaceted disease in the sense that everybody starts out with normal appearing retinas. And then over time, patients who develop the disease will develop these deposits called drusen, little yellow dots that we can see on the retina when we look in and can image them with various imaging modalities. And then a percentage of those patients will go on to further degenerative changes called geographic atrophy, in which their central vision will be lost. Conversely, other patients will develop an abnormal blood vessel, which will grow in the center of their vision. They can also [indiscernible] vision. And in fact, some people will develop both forms of what we term late macular degeneration. Now of course, when we look at the impact, especially of geographic atrophy, on vision in these patients, the truth is, for a little while, they can maintain central vision. So they will lose a lot of the peripheral vision around the center, so they can still kind of function. You can see on this kind of [ protect ] going. But then over time, those will get worse. And macular degeneration with the Beckman Committee many, many years ago to ensure that we have a good definition of these various stages of macular degeneration. We call early AMD those patients that have relatively small drusen, between 63 and 125 microns in size. And then in some patients, those drusen will get larger than 125 microns or even larger, and we call that intermediate. And then as I said, a portion of these patients will continue to progress to these late stages of geographic atrophy or blood vessel growth called neovascular AMD. And the interesting thing for ophthalmologist and for retina specialist, we have these unique imaging tools, not only in terms of [indiscernible] which we could actually take a very precise slice of the retina and see these various stages of the disease very accurately and precisely. So it gives us enormous power in testing modalities and treatments and following our patients in the clinic. So now if we look at the percentage of patients that go on to develop these advanced forms, again, about 70% over 10 years will develop some form of these late complications or late -- end stage of macular degeneration. And interestingly, although our therapies, as I'll show you in just a second, are all focused on neovascular AMD, the actual percentage or the prevalence of this late degenerative form that we call geographic atrophy is the same as for this neovascular form. So there's lots of patients out there who are suffering this vision loss that we call geographic atrophy. As I said, we have therapies for the wet form. They've been around for about 15, 20 years now. We primarily use drugs against vascular endothelial growth factor, VEGF. And it turns out that they can be very effective in reducing the complications of these abnormal blood vessels that grow under the retina in this late stage of macular degeneration. Unfortunately, we have no therapies for any of what we call the dry form of the disease [indiscernible] or, of course, these later stages, where patients start to lose their central vision, we have no therapies for these patients whatsoever. And the result of that is that, interestingly, overall, when you look at the whole consort of dry eye AMD, intermediate and advanced, there's a huge number of these patients because, again, lots of patients will develop disease and then go on to develop the late stages. We classify all of those patients as dry AMD. And you can see here that, on average, anywhere between 4 to 5x more patients will have some form of a dry disease versus the wet disease. So again, lots of patients out there for whom we have no treatment whatsoever. Again, the global prevalence of this is also age-related. So as you look at our population getting older, especially this late degenerative state, geographic atrophy, you can start to see that the prevalence data is really, in some ways, overwhelming in the sense that if you get to be 85, about 5% of the population will have some form of geographic atrophy. We know now that our population is aging well into their 90s and about almost 1/5 or 1/4 of the patients will have some form of this very severe degenerative stage of the disease. And again, as I said, age-related and the prevalence of both of these diseases is the same. So a large number of patients that are going untreated because we just don't have any treatments for any of these dry forms. And they're equal, whether you go to Europe, whether you go to Britain or the United States, again, this is a disease that affects primarily European descent patients in terms of geographic atrophy. And of course, we see this in Europe and other parts of the world. in which these incidences are very similar. So again, large number of patients that we have out there. Now I give this slide only because it points out the challenge we have in treating these other forms of the diseases. Right now, when we say we have a treatment for the wet form, we do, but that treatment really involves putting a needle into the eye on a repeated basis. So our treatment right now for the wet form is taking this needle, putting it into the eye, up the eye, you put the needle into the eyeball, you actually inject the medicine. And then unfortunately, that drug will wear off. Anywhere between 4 to 6 weeks, sometimes 2 months, we'll have to reinject and sometimes for the entire life of the patient. So you can see that while it's very effective in treating, it really is what we call an enormous treatment burden in terms of patients. So if we could develop therapies that will be effective for the dry form as well as providing an alternative mode of delivery, that would be an outstanding unmet need that we have. Clinical trials assessing the role of various vitamins, lutein, zeaxanthin exclusively in terms of reducing the wet form of the disease. And when you try to look at the impact these vitamins have on preventing this dry degenerative form, geographic atrophy, it essentially has no benefit whatsoever. So again, all of these patients are out there, lots of patients with dry AMD, patients progressing, and we have absolutely nothing to offer them whatsoever. And we know a little bit about the pathology mostly from immunohistochemistry of the human eyes, and we were able to identify -- [ Greg Hayman ], in particular, was able to identify that in these drusen, which, of course, is one of the signature lesions in macular degeneration, a large cohort of proteins, very complex proteins, they are related to complement in many ways, but also related to just injury of a cell layer called the retinal pigmented epithelium. So when the retinal pigmented epithelium gets injured, it starts to secrete lots of proteins, a lot of the lipoproteins, and we can detect that in terms of pathology specimens, indicating that there is something wrong with the cellular called the retinal pigmented epithelial and its ability to be injured in macular degeneration. Now interesting, the genetics of macular degeneration, very complex. Yes, there are genes that are involved in the complement cascade, but there are also genes involved in lipid transport, genes involved with an extracellular matrix protein called HtrA1. And the essence of all of this is that the genetics play a part of the puzzle but not the entire puzzle. And we think -- many people think that it accumulates in multiple different injury kind of stimuli and the RPE reacts by causing drusen formation, other responses. So it's really a response to injury that these genetic mutations kind of predispose you to. But ultimately, they all seem to go through similar common pathways, and that is kind of an injury response of the pigment epithelium. So again, this is kind of our working model of what we think macular degeneration is driven by. We know, for example, that there are environmental factors. Smoking, for example, is a very big risk factor for the progression of macular degeneration. Why? Because again, it causes injury to cells. Same thing true with diet. Same thing true with some light exposure. All of these, we think, are environmental stressors on the cell called the retinal pigment epithelium. You lay on top of that some genetic factors, some other forms of damage and we think that, that's the driving force of the degeneration of the retina and, of course, macular degeneration. So now when we think about where we are in terms of our ability to develop drugs for the dry form, it's been a big challenge. Part of the reason is that with the wet form, the response to treatments were so successful, patient got better vision. So from an FDA regulatory perspective, that was an easy way for these drugs to be approved. We simply were able to show that in these groups of patients that had wet AMD, we gave them the injections once a month, and their visions got better. But in a degenerative form, it's hard to show improvement. So I was very fortunate to work closely with the FDA on several meetings with them. And we were able to convince them that as these areas of tissues enlarge, as these areas of degenerative tissue expand, that's a bad thing. And so they were able to then come to terms, and they were allowing us now to look at a reduction in the expansion of this area of degenerative tissue as a provable endpoint for this geographic atrophy or the degenerative form. So it's allowing us now to begin to start to interrogate therapies to try to slow this degenerative process by slowing the rate of expansion of the dead tissue that we see in these patients. Now there's been lots of attempts to kind of solve the puzzle. First puzzle, of course, what's really focusing on complement. And lampalizumab was the first drug. It was an anti-factor D. It's an important molecule in the complement cascade. And there was a large, extensive study that was run by Genentech, and it tried to show the injections, again, injections into the eye, could slow this progression or the development of expanding geographic atrophy, targeting a complement. Unfortunately, the results of that study showed there was absolutely no effect. So the patients who are receiving these injections of an anti-factor D or trying to shut down or reduce the complement system, in the end, had no effect whatsoever on the slowing of the rate of the expansion of this degenerative tissue. So that was kind of a disappointment, but that's where we were. Now more recently, there's been other attempts focusing on various effector molecules of the complement system. [ Anti-factor V ] finished a Phase II, and they did show in the Phase II that there appear to be some slowing of the rate of expansion. An ongoing Phase III study is still ongoing. We don't know the results of that, but this was the first time we start to see some early signs that perhaps an anti-V might give us some benefit. Similarly, a parallel trial was done with an anti-complement 3 molecule. And there, too, there seem to be some slowing of the rate of the degeneration of this tissue. And of course, the whole key is to how much slowing can you get. And this is somewhere around 20% slowing. So while we think it could have some value, it's not what we're really looking for. What we're really looking for is a more substantial effect. But these were the first time in Phase II trials and now in Phase III that we start to see some early signs that there might be some ways to slow the process down. And that is just a quick overview of the landscape of where we are with macular degeneration, in particular, the facts of dry macular degeneration, which for us, as practitioners, is an enormous problem that our patients are facing.

Next, we'll be hearing from our own Vice President of Research, Dr. Mary Hamby. She'll be leading us through some of the background of the rationale we presented for why we're in dry AMD and paying particular attention to the data generated in Dr. Ratnayaka's lab. Mary?

I'm happy to be here today to tell you a little bit why we believe that targeting sigma-2 [indiscernible] with small molecule point out from Karl's talk that several biotech pharmaceutical companies are pursuing, as he mentioned, invasive methods that require intravitreal injections, gene therapy approaches and even cellular replacement therapy approaches. So we're excited about the fact that at Cognition Therapeutics, we have small molecule pools of evidence, which we believe that targeting sigma-2, maybe a promising therapeutic approach. So importantly, the sigma-2 receptors are expressed in the target tissue, the retina, and more specifically in the retinal pigment epithelial cells that Karl mentioned earlier. We also know there's a large degree of overlap between the biologies that sigma-2 targets or regulates and those that are disrupted in dry MD. Other independent laboratories have also knocked down the sigma-2 receptor, TMEM97, and found it to be protective in rescuing retinal pigment epithelial cell death. So that was very exciting to see. There's also a human genetic link, which I'll go into in a little more detail on the next slide, that links the sigma-2 receptor to dry MD. We now have internal data, both clinical biomarker support as well as preclinical data, which I'll take you through, that indicates that sigma-2 receptor modulators may impact key proteins and pathways linked to dry MD and can then restore RPE functioning. So if you go into the genetic data, this is very exciting. As Karl mentioned, there is a slew of genetic risk factors for dry MD, and many of them are complement related. But what many have overlooked is the fact that TMEM97, the sigma-2 receptor, is also genetically tied to dry MD. So what's shown here, there are large-scale, genome-wide association studies by several independent groups that have now identified a single nucleotide polymorphism and the TMEM97 locus that confirms a decreased risk of dry MD. So now moving on to our clinical biomarker data. We leverage the fact that we had in our clinical trials, as a 28-day trial, COG0102 and our SHINE trial which is the 6-month clinical trial in mild to moderate Alzheimer's patients. This is an age population where we had biofluids from these patients, both plasma and cerebral spinal fluid. And what we did is we did large-scale proteomics analyses to identify the proteins that were altered with treatment with the sigma-2 receptor modulator, CT1812, compared to patients that were given placebo. From this large-scale proteomics analyses, what we identified was a set of proteins that were differentially expressed in these biofluids. And from that, we took that list of proteins and did what was called an unbiased pathway analysis. And what this does is it will tell you what those proteins, which pathways they're involved in. And when we did this, this was done in our Pittsburgh laboratory at Cognition, the group identified the top disease ontologies. And what we found was that the top disease ontology was geographic atrophy and sixth on the list was macular degeneration. So this was very exciting for us because this provided early proof of principle that CT1812 being tested at investigational trials for Alzheimer's disease has the capacity to alter proteins and pathways linked to dry AMD and geographic atrophy. We dove further into the proteomics data because we wanted to identify these proteins and understand how they're linked to the proteins already known to be disrupted in dry AMD. And there's a slew of literature that have done proteomics studies in dry MD patients. either in plasma, the Bruch's membrane or other tissues. And what we found was that there was a set of proteins identified. And we did a [ streaming ] pathway analysis of protein interaction analysis and found these proteins to be highly connected, statistically significantly connected with one another, and we identified some key pathways, including pathways involved in cell trafficking. But before I tell you about our preclinical data that we just presented at the ARVO meeting in Denver, Colorado, I'd like to go into a little more detail about the cellular and molecular pathogenesis of dry MD. So Karl told you a lot about this already. But on this slide, I want to point out, you can see the RPE cell layer and how the photoreceptors sit proximal to that layer. And as Karl mentioned, RPE layers, supportive layer is quintessential for proper functioning and health of the photoreceptors. So in early dry MD, drusen, the deposits of lipids and proteins, as Karl mentioned, they accumulate. This can cause the thickening of the Bruch's membrane, and this can disrupt the cellular architecture of the retinal pigmented epithelium, causing disruptions in the cell function. Oxidative stress and toxic proteins can precipitate this. And one of the key functions of the retinal pigment epithelial cells is to take in these photoreceptor outer segments that are shed from photoreceptors as part of the normal visual cycle. And to recycle them, and this is part of the normal -- a normal homeostatic process that occurs. So moving on to our preclinical data. We worked in collaboration with Dr. Arjuna Ratnayaka to understand whether or not sigma-2 receptor modulators could restore the ability of RPE cells to recycle photoreceptor outer segments. So let me take you through the intracellular compartments of the trafficking that occurs in the RPE cells. So as you can see, there's early compartments photoreceptor outer segments get taken in by the RPE cells. They started off in these vesicles, the early compartment Rab5 positive vesicles. They move to Rab7 positive vesicles. And then they move into the lysosomes that are labeled with an antibody for LAMP2. And then lastly, they move to autophagosome bodies that are LC3B labeled. What we did with Dr. Ratnayaka in his laboratory, we took polarized mature RPE cells and expose them to toxic A beta oligomers. And what his laboratory had previously shown was that A beta oligomers disrupt the ability of RPE cells to take in and traffic the photoreceptor outer segments. And he had nicely elaborated upon the kinetics of this phenomenon. So what you can see here is that, over time, an untreated cells in the blue, white-blue line, you can see that the photoreceptor outer segments move from the LAMP2 positive lysosomes, and they move into the autophagosome bodies. So that's what's the normal process in the RPE cells. Now with A beta oligomers added to these cultures, this disrupts the trafficking, and you see this in the red line. So what you can see here is instead of the photoreceptor outer segments moving to the autophagosome bodies, they get stuck in the lysosomes. Now what was quite remarkable to us and exciting was that with -- in the presence of CT1812, sigma-2 receptor modulator, this, as you can see here, is a dark blue line, very much resembled the healthy control situation, even in the presence of A beta oligomer. So we're very excited about that. What's not shown here, this is data showing with CT1812, but we also did a split 2 other chemically distinct sigma-2 receptor modulators. And they were also able to preserve the functioning of the RPE cells in the presence of the A beta oligomers. But we were very interested in understanding whether this effect was specific to disruption of this process by A beta oligomers or if it was more generalizable to stimuli it or also play a role in dry MD such as oxidative stress. So what we did next is we exposed this in the same system. Instead of using A beta oligomers as the toxic stimuli, we chose oxidative stressor, hydrogen peroxide. And as you can see here in the orange line, in this case, hydrogen peroxide disrupts trafficking early on. And you can see that very quickly, in 12 hours, that the photoreceptor outer segments are already in the autophagy bodies. And again, to take you through the control, the healthy control cells, that doesn't occur until 48 hours. And if you're looking at the right and the LC3B-positive autophagosome body compartments. And what you see here is that CT1812 again resembles the healthy control situation. So the light blue is the untreated. And you can see that with hydrogen peroxide and the presence of CT1812 in the dark blue line, the lines closely overlap. So again, this suggested that sigma-2 receptor modulators can preserve this homeostatic function of RPE cells disrupted not only by A beta oligomers but oxidative stress. Additional details on this data can be seen on the ARVO virtual platform, and that's available through June 30, and it can also be found on our website. But collectively, this data expands beyond the previously elaborated mechanism of action of CT1812 and suggests that CT1812 may be protective against oxidative stress as well as A beta oligomer toxicity and age-related degenerative diseases. And as I mentioned earlier, in conjunction with our clinical biomarker data and the genetic evidence does support advancing sigma-2 receptor modulator to the clinic. One thing we did need to check, though, before we move to the clinic was whether we could achieve therapeutic levels in the retina with an oral administration. And that data is shown on the left. As I alluded to earlier, as you can see here, the levels in the retina shown in orange are well above our 80% receptor occupancy line. And why is that important? What we know from our in vivo animal models is that when we achieve greater than 80% receptor occupancy exposure levels, that confirms efficacy. So we are very excited about advancing CT1812 to the clinic for a Phase II proof-of-concept study for dry MD. And again, as Tony took you through earlier, you'll see our clinical trial design [indiscernible] for you on the right. Thank you.

Great. [Operator Instructions] So now we have several folks who are going to join Karl and Mary and have a panel discussion. So we have Dr. Ratnayaka, Dr. Lim, and this panel discussion will be coordinated by Dr. Robertson.

We have just heard exciting data. Let's turn our panel for their comments. Dr. Ratnayaka, can you tell us what you think is particularly interesting about the material that Mary has just presented about the findings that were presented about CT1812 in the ARVO abstract and poster?

Thank you, Dr. Robertson, and thank you for inviting me to this panel. So I think the internalization and degradation of [indiscernible] receptor targets linked with their renewal is an important feature of healthy RPE cells, as Dr. Hamby so eloquently described. And we have shown previously how distinct AMD-linked disease mechanisms, such as impaired autophagy and oxidative stress, interfere with this homeostatic trafficking and degradation of these [ kinds ]. Now the data that was presented at ARVO show for the first time how to [ start ] AMD-linked disease pathways, namely, oxidative stress and A beta-mediated pathology, can be effectively rescued by a family of the sigma-2 inhibitors. Now to my knowledge, these findings are the first to demonstrate the targeted rescue of this specific patient, indicating how multiple disease media -- regardless of their modes of points of action, can be rescued by [indiscernible] as Dr. Hamby said, the 2 pathways, so the rescue of premature photoreceptor outer segment trafficking to mature lysosomes and autophagy bodies under conditions of oxidative stress, and the rescuing of photoreceptors from being sequestered in mature lysosomes and/or prevention of autolysosomes from forming when RPE cells close to A beta. Now both these scenarios can lead to the accumulation of [ incompletely ] degraded photoreceptor outer segments within RPE cells. This is the source of water presence, which is a well-established clinical endpoint in assessing GA patients [ by autofluorescence ]. And the final point I'd like to make is this is an interesting one because the rescue of A beta-mediated lysosomal defects also has implications, I think, for understanding neuronal dysfunction in the brain because amyloid beta is a major driver of Alzheimer's pathology, which is -- where A beta is known to accumulate and impair lysosomes or neuron [indiscernible] as well as the blood brain barrier. So that could be a beneficial effect for hippocampal neurons as well. So I think this is really intriguing and great data.

Thank you. So Mary, would you like to talk about how Cognition identified the link between the effects of CT1812 in the brain to those in the eye and the retina?

That's a great question. We identified sigma-2 modulators from a screen in the [ renal cells ], it was a phenotypic assay where we identified that sigma-2 modulators could block the ability of A beta oligomers from binding to neuronal synapsis. And we knew from the literature from Arjuna Ratnayaka's group that A beta oligomers also played a role in dry MD and could disrupt key functions. So that was one entry point to how we've started thinking about could sigma-2 modulators be potentially beneficial for dry MD? And then the rest is really what I described in my presentation, the genetic link. There's some literature out there that shows that sigma-2 biologies have a common overlap with those disrupted in dry MD. And lastly, the proof-of-concept data I mentioned from [indiscernible] group that showed that TMEM97 knockdown could be beneficial in restoring RPE cell health. And so really, we're really excited now that we have their clinical biomarker data as well as this new preclinical data with Dr. Ratnayaka that really does support sigma-2 modulators as being a potentially beneficial therapeutic for dry MD.

And the correlation is just really amazing. And it just shows that there is truly a relationship between the brain and the eye.

What's amazing to me is that with aging, you get Alzheimer's, right, and you get these amyloid plaques that build up. And that with macular degeneration, you're now also showing the A beta oligomers that also build up. But this to me is the first drug that is actually getting to the heart of the matter, removing it, because all the other drugs are like anti-inflammatory, but they're more of like a mass effect, if you will, like anticomplement C3, anticomplement C5, but they're not actually getting to what's accumulating and their helping RPE function. I think later on, we're going to get to some of the other drugs that maybe help the mitochondria help digest and help the RPE function better. But I think this is the one that really gets at it. That lab data, to me, was really exciting. I mean that really just, I think clinches, it. So congratulations. I think it's great.

Yes, I would definitely agree. I think when we talk about the issue and that is these cells, the RPE cells, have to bear a lot of kind of jobs in terms of ingesting every day a large amounts of these outer segments. And as Jenny says, as we get older, the RPE does not get replaced. We have the same RPE cells that we were born with. And so the idea that we're going to be hopefully providing some additional benefits to help them digest these enormous amounts of outer segments that are really required to be digested, to me is, a very exciting way to interrogate a potential therapy for dry macular degeneration.

Karl, do you think that if you gave somebody this drug, assuming it would work, right, and it gets rid of the stuff, do you think the drusen go away?

Yes. I think those are intriguing. Those are some of the nice things that we have in retina, right? Unlike the brain, where it's difficult to image these little small particles, here, we have the opportunity to even fairly early on in the trials to try to look morphologic changes that could be impacted by this trial.

In fact, you could see on autofluorescence. We can maybe look at those hypo dense scores on the OCT that are higher risk for going on to GA. So I think there are a lot of biomarkers that we could use to actually see if the thing is actually doing what it did in the lab. I hope it is.

Yes.

So Dr. Ratnayaka, do you have some comments on the relevance of these in vitro results when looking at the broader disease biology?

Thank you, Dr. Robertson, Yes, absolutely. I think the broader relevance, I think, is that functional RPE cells need to exist for these compounds to have an effect. I think as beyond a certain level of RPE damage, potential effects maybe suboptimal or ineffective. But having been said that, the geographical or the location-specific nature of RPE atrophy in GA patients, I think, enables the capability to extend the potential use of this compound even in otherwise advanced cases. So in other words, what I'm saying is that the remaining functional RPE cells beyond the immediate margins of the GA lesion may be prevented from further damage or have the effects of slowing down further damage by these compounds. So histopathological studies of [indiscernible] tissues by [ Sachs ] and colleagues, now many decades ago, showed a graded zone of damage extending outwards from the lesion margins. And the fact that the S2R modulators can rescue impairment of the homeostatic trafficking and degradation of outer segments from more than 1 damage-inducing pathway, I think, bodes well because it suggests a wide therapeutic window in RPE cells. I think in general, that mode of action suggests that treatment at earlier stages of GA is likely to be more effective, and potential effects in the RPE monolayer can be evaluated by possibly fundus, although these don't necessarily provide nuanced information on RPE health per se, such as, for instance, the extent of oxidative stress or A beta-mediated pathology. So I think identifying suitable patients is therefore key to testing the efficacy of these compounds, I think, in real-world situations.

Well, that's a great lead-in. We're now going to turn more to the clinical discussion for the panel. And so we're interested in having Dr. Lim talk to us a little bit about what are the other therapeutics that are in late-stage development and how she sees that the opportunities might be for this molecule.

Happy to do that, Stella. As you heard from Karl's presentation, a lot of the therapeutics now for dry AMD are really centering upon complement, the anti-C3, anti-C5. And right now, those are all, as you said, Mary, they are injectables. And so it's very limited what can be done right now. So we can allude to this anti-C3, Karl, you had talked about the FILLY study, which was the pegcetacoplan molecule, which is an anti-C3 binder. And so this drug in the Phase II showed promise. It showed decrease in lesion growth rates up until 12 months. And then patients were taken off the drug so that at month 18, the decrease in the growth rate was smaller. So that showed that the drug was actually doing something during the 12 months that they were on it. So then that went forward to do DERBY and OAKS, which were the Phase III. And I think you and I were like hoping that it would work, right? But unfortunately, in DERBY and OAKS, which is the Phase III pivotal trials, 1 study did show decrease in the growth rate, that was the DERBY, but then the OAKS did not. It just missed it in terms of statistical significance. And at ARVO, it was shown that perhaps there was some imbalance in the groups. Perhaps there was perhaps more eyes in the placebo group that had factors, risk factors, that were not as high for progression. And that in the treatment arms, there were perhaps more eyes that had higher risk factors for progression. But again, that's a post-hoc analysis, who really knows. But the bottom line is the 2 studies did not show the same result. So that study is kind of in limbo right now in terms of the drug moving on. In terms of another drug that is an anti-complement, we can look at anti-C5. And again, Karl, you alluded to that in your presentation very nicely, which was, I believe, you're alluding to GATHER1, which was the drug which is an aptamer, and it was avacincaptad pegol, a mouthful, also known as Zimura, and that has been shown to work in the GATHER Phase I. And as you and I know, we are really happy, right, to see the slowdown in the growth rate. The side effect though was the onset of choroidal neovascularization. And although you can treat choroidal neovascularization, it's something ideally we don't like to see. And so going forward, avacincaptad pegol is being studied in GATHER2. And in GATHER2, these patients are continuing in the study, so they continue to get the anti-C5. If they get the choroidal neovascularization, they can get the anti-VEGF because it was manageable in GATHER1. So all the bets are still off. We're still looking forward to that and seeing what the results are because the GATHER5 results -- the GATHER2 results rather are not yet out. So then we think, well, what other drugs are there? While there is the HtrA1 then being studied in Gallego, a Genentech drug. That's very early on right now, and so no results are yet available. But again, you alluded to the HtrA1 being involved in dry AMD, so that there's biologic plausibility for this. It makes sense, right, to try an anti-HtrA1 drug. There are also another -- there's another anti-C3 drug also out there. And that is NGM's drug. And NGM, I believe, will be finalizing their data closing out by the fourth quarter this year. I just talked to somebody from there because we're also in that study. So again, hopeful but we don't know yet. And again, these are all in injectables. And today, we hope that some of these drugs will pan out, but we just don't know. There are a lot of other drugs that are still early in development. At ARVO, we heard about gene therapies that are also being used. Again, very early on, suprachoroidal drug delivery to get the drug there. Too early, it's still Phase I/II. So they're not as far along as the anticomplement type drugs that are there. And then lastly, I want to bring up another drug I think is kind of interesting, elamipretide, right? So elamipretide works on the electron transport chain, and it hopes to improve the transfer of electrons to help the RPE cells be more functional just like your drug, 1812, and help to -- help the RPE digest all of these abnormal things in there. And it's a subcutaneous [indiscernible]. Side effect is eosinophilia but it goes away, and we don't know yet. That's still very early on. So I guess to sum up, Stella, there are a lot of drugs in development right now. But probably the ones that are most further in line of development are the anticomplement, but they are injectables. So if I were to look over at this landscape, I would say if you had an oral drug that works, that would be the simplest. You don't have the risk of endophthalmitis, which Karl and I have to deal with on a day-to-day basis, or the risk of endophthalmitis. It is rare, less than 1 in 1,000, and then risk -- possibly other risks related to the injection.

Well, I think, Jenny, your point earlier, and that is the problem we're having is that we have this genetic data. Everybody then went to the complement system. And of course, we had a big failure in lampalizumab. And I think the results we're seeing, as you say, there's some maybe wins, but maybe also some -- and I think the point you made earlier is it's not really getting to the true pathology of the disease. The complement system is a reactive pathway that's reacting to something that's happening in the RPE. And as we heard, there's lots of evidence to suggest that this abnormal trapping is really what's kind of the generator ultimately of the process. And so if we can change that dynamic, that pathology, I think we're getting to the real heart of the matter rather than trying to treat some of the reactive indicators that, I think, the [ complement estimate ]. So -- and in that sense, when we look at the data, there's reason to believe that in this case, an oral therapy could actually be helping the ultimate state of the RPE, which is what we're really trying to achieve.

Absolutely agree with you. And then maybe a side effect is you get Alzheimer's. Has to be all good for our patients.

That's true.

I think if I can just add another comment around that. It's a complex disorder, and it's unlikely that any one therapeutic modality or target approach would be all-curing, right? It's very likely that there will need to be a lot of different therapies targeting different proteins in different pathways to fully treat this disease over time.

That's absolutely right. I mean we see it in wet AMD. Going a little bit off topic, but in wet AMD, we're doing [indiscernible] plus anti-VEGF and maybe getting more efficacy and durability by doing that. So Karl, let me ask you this question. Dr. Ratnayaka, which became about the importance of this 1812 molecule, and perhaps rescuing the RPE that is not quite dead yet, right? And so I know you've done a lot of work on low-level [ illuminants ], you've done microperimetry. And in addition to autofluorescence, we know that those kind of probably like falling off the path in that little penumbra of RPE, almost a number of death of those RPE cells. So perhaps that might be a good way to see the effect of 1812 clinically by doing these [indiscernible]. What do you think about that?

Yes. I think one of the, again, one of the big values we have in retina is not only can we look at the anatomy in exquisite detail, but we can also interrogate the function in exquisite detail. So we can take very small pieces of light and shine them on very accurate areas of the retina and determine their function. So we have ways to really interrogate. And then as we talk about at what point will the cells respond even very early on in a trial. So there's reason to believe that because we can interrogate both the anatomy and the function, we can start to really get to this question of, what are the right patients that need to be treated, when do we need to treat them and what's the benefit that we hope to get.

And with this drug, you would rescue, right, you would rescue those areas and then you would prevent the damage maybe in the areas beyond. And then as to what Mary said, combination there be then maybe in the center where you've got the GA, you can use therapy to restore. So you could actually use all of these together, restore the function there, rescue the ones that are already dying, and then prevent the progression on, because it's genetics, right? It's genetics and a beta of Alzheimer's that are going to keep forming the older you get.

Absolutely.

And the older you get, the more you have stress as well, right, which is another factor, and this molecule has some anti-inflammatory activity, and therefore, it can be useful through that pathway. So Dr. Csaky, would you close us out here talking about considerations for clinical trials for recruitment, for trial design, maybe some of the key endpoints.

Yes, absolutely. Jenny and I are in lots of clinical trials. We're having lots of clinical trials for dry AMD in particular. And when we think about what are some of the hurdles for getting patients in. As we talked about, these patients are older, right? And so when you're talking about an experimental therapy, you want to make at least the kind of burden on them having to come in for a trial as low as possible, and we're having to do injections which, now all of our present therapies that are really more advanced, require the patients to come back every week and every 2 weeks for injections. So in a way, if we can give an oral medication, that already lowers the burden and this kind of discussion we have, not only with the patient, but with their caregivers, everybody else. So in one way, it simplifies everybody's life. That's an enormous benefit. It also reduces some of the fear that people have. You can imagine getting a needle into your eye is not something that people want to happen. And so there is already, even though they know that there's no treatment for this disease, they know that it's eventually going to get worse, there is a natural inclination when we talk about what is the risks. There are some significant risks, putting a needle in your eye, as opposed to an oral therapy. So again, these kinds of discussions that we have to have with patients and their caregivers, some may go away when you think about an oral therapy. And of course, the other thing that I think we're getting excited about is the fact that if we have new modes of action, it excites us because we've been kind of down the complement system, we've seen the results, which, while we're hopeful, are not necessarily something that we really are like blown away by. So the idea that we're going to be interrogating a novel pathway is something that a lot of investigators will be interested in. So when I think about, as someone who is involved in recruiting patients and having these discussions, and I look at what some of the barriers are, this, by far, has the lowest barrier that I can imagine of recruitment of patients. Jenny, any thoughts on that?

I would agree as well, Karl. And also in terms of the burden of care for families to bring them in. So patients, even if they are going to come in and they can drive on their own, if they have to give a shot, as you know, a lot of them are reluctant to do this by themselves. So they'll bring in a family member who then has to take a day off work or their spouse would have to drive them in. Whereas if it's an oral drug, there's drive in and drive back home in the clinical trial, so I think it would be easy. And I think, as you said, there are a lot of functional markers, tests that we can use in the clinic, and also anatomic markers, so that we can get an objective end point that we can measure, which I think is really important for this drug just to its effect.

It's a really exciting time right now in retina. So Tony, can you tell us a little more about the plans for the clinical trial?

Sure. So as you know, we're deep into development in Alzheimer's disease, and we plan to leverage the safety data from those studies in that most of those patients are of a similar age group as the patients that will be treating with dry age-related macular degeneration. So this study will be a study of about 200 patients with dry AMD and GA, both foveal and non-foveal, and we'll be looking as a primary outcome at the change in size of GA in these patients with treatment with CT1812 for 1 year. So we're planning to start this trial by the end of this year.

I just wondered in terms of assessing patients, whether you are going to use multimodal retinal scans or you're going to perhaps look at fundus autofluorescence and so on, whether there's a preferred way of going forward to get to your kind of end points?

Yes. So as we discussed, that's one of the beauties and again, I think we'll hear about a primary endpoint. But clearly, what we have in retina and in many of our trials, we do multimodal imaging. It's very easy. It's not invasive. So we can do it on all our clinical trial patients. And those include anything from fundus autofluorescence to OCT, even to OCT as part of this trial as well.

Yes. So as those things are secondary measures within the study, primary outcome is, as you mentioned earlier, this has already been discussed with FDA. So other studies has a potential for being a pivotal measure as we seek approval. So that's the general design of the study, and we'll be talking more about that in the next many months.

Well, thank you for sharing that with us. We really appreciate it. So at this time, I'd like to thank all the panelists for their great insights into how we can develop a new therapy for treating this unmet medical need, dry AMD. And I would very much also like to thank our viewers and turn it back over to Lisa.

Stella, panelists. Thank you.

Great. So one of the first questions that came through was asking about the potential market size of dry AMD. Lisa, do you want to take that?

Certainly. Thank you, Tony. So 1 way to look at markets, of course, is how many people have this problem, right? In AMD, Karl referenced this broadly, wet and dry AMD. You're talking about a rough ratio of 15% of the patients have wet, something like that; 85% of the patients have dry AMD; 11 million, 12 million patients. What we're talking about are very large populations, 4 million to 5 million patients with wet AMD and the balance with dry AMD. You will recognize that, that's multiples of the size of the AD market. So this is a pretty significant category. Now as yet, there are no drugs for dry AMD. If we look at wet AMD, we know [Audio Gap] products, making it a very, very large category. How the drugs in dry AMD create a commercial market is before us. It's a function of the efficacy profile of the drug, the safety profile, the cost of goods, the success of the companies at educating physicians as to who the right patients are, and there are many elements to be determined as we go forward with our program and as other companies go forward ahead of us. So at this time, we're very confident that this is a large commercial opportunity, but we're not yet ready to put out a size to indicate what it can be. We only can point to the wet AMD community and the fact that this is a much larger group of patients than we see even in Alzheimer's disease.

Great. So we've had several questions coming through about the overlap between Alzheimer's disease and dry AMD. So I thought perhaps we could have Dr. Csaky talk a little bit about what we see clinically, and then we can ask Dr. Hamby talk a little about what we know and the biology. Dr. Csaky?

Yes. So as you heard, I mean, obviously, the dry AMD, kind of the numbers are much larger. And of course, part of that is the fact that our accuracy on making the diagnosis is so high. I mean we have these tools that we can look in and make the diagnosis at various stages of the disease. What we know from epidemiology is that in patients, once they have had the diagnosis of Alzheimer's, especially if this more severe dementia, we rarely see those patients. So we don't know the association between people who have severe Alzheimer's and AMD, mainly because most of those patients at that point are not coming in for a routine vision test. But the converse though has given us some interesting epidemiology. If you look at patients who have AMD, they are at somewhat higher risk for developing Alzheimer's at some point. So there are some associations and [Audio Gap] of those. But even if you take things like just your lifestyle and everything, there's still an increased risk of developing Alzheimer's, if the diagnosis of macular degeneration has been made in you. So there is some associations.

Great. Thank you. Mary, perhaps, you can talk a little bit about the biology in there?

Thanks, Tony. Yes. Dr. Csaky already mentioned age, right, there? So both Alzheimer's and age-related macular degeneration both have a common, they are degenerative conditions in an aged population. And moreover from both the literature and from human genetic data, we know there are several biological pathways that are shared in common between these 2 indications. The complement pathway is one of them both for Alzheimer's and dry AMD. As maybe you are all well aware, complement pathway is highly pursued as being a potential therapeutic avenue that could be promising to the patients. We also know inflammation is a common denominator between both indications. And lastly, we know oxidative stresses. Oxidative stresses presenting in both Alzheimer's in our brains as well as in the retina in dry AMD patients. And the disruption of cellular homeostasis and [indiscernible] and cell trafficking are also common denominators. So we're very excited that the Sigma-2 modulator data that we presented suggests that we can restore cellular homeostasis now in dry AMD as well as what we have previously shown in Alzheimer's in our preclinical models. Thank you.

Great. So we have a couple of questions and other things in development, particularly complement therapies and C3. So perhaps we can have Dr. Lim talk to us a little bit about how physicians will look at using a drug like CT1812 in the presence of already proved complement-mediated factors.

Yes, Tony. I believe that the anti-C3, anti-C5 drugs, which are injectables, if they are effective, would probably be used. Again, the caveat is, if you have an oral drug that works just as well, personally, patients as well as physicians would rather prescribe an oral drug and the patients would rather take an oral drug for the following reasons. One, you obviously don't have the risks of injection into an eye. Secondly, you don't have to come in every month for the injection or however often you have to get the injection. And then third, you don't have the risk of choroidal neovascularization, which is the side effect of the anti-C3 and anti-C5 drugs. Although it can be treated, that again necessitates yet another injection of an anti-VEGF to counteract the side effect of anticomplement drugs. So personally, as I said before, I really do believe that the CT1812, if it works just as well as a complement inhibitor, would be my preferred choice. Oral drug is so much easier.

Great. So speaking of oral drugs, we have had some questions around the safety and tolerability of CT1812 and Sigma-2 modulators in our experience. And as our experience has been exclusively with CT1812 and in Alzheimer's disease and now with patients with dementia with Lewy bodies, one advantage of being in these populations is they are also aged than the normal population. So we have very good information [indiscernible] drug are tolerable in these patients. Obviously, we've only been in [indiscernible] patients. So new side effects will pop up [indiscernible] at the dose levels that we were exploring Alzheimer's disease and dementia with Lewy body. So now we have a question for Stella. So the question is commercializing and developing other ophthalmologic drugs. Tell us a little bit about what you see as appealing or not appealing about CT1812.

Thanks, Tony. I've followed the company for a number of years, and I'm really impressed by the depth of science and the data-driven approach that you've taken to developing treatment for neuro protection. And for CT1812, it's really an attractive opportunity for treating dry AMD. It is completed, but as you said, the Phase I/II clinical studies in aged patients, in Alzheimer's patients, and it shows safety and tolerability in this patient population as an oral dose. It also shows some target engagement and efficacy in these studies through its biomarker indications. And then recent preclinical evidence has really suggested very strong rationale for going into the eye for dry AMD to protect the RPE cell and the photoreceptor cells and the possibility of also damping down the inflammatory process. So I think these things combined together, along with the novelty of oral delivery, the physician as well with patient load, that it's a really promising opportunity for ophthalmic development for dry AMD.

Thanks, Stella. Dr. Ratnayaka, can you expand a little further upon the links between AD, dry AMD, and perhaps what we know from larger?

I would be happy to. Thank you, Tony. So there's been some recent work shown by Dr. Maya Koronyo-Hamaoui from Cedars-Sinai, where she looked at eyes of patients with mild cognitive impairment and showed an associated increase with severity where they have increased levels of amyloid beta accumulating in the retina, which is really interesting. And I think that goes back to that first question that was asked about these links. We know that amyloid beta is a major driver of Alzheimer's disease. And also, it accumulates in our retinas as we get older and is associated with increased [indiscernible]. And I think that recently, Dr. [indiscernible] flagged up a paper that was published by Professor [indiscernible] group, showing again the importance of lysosomes as sort of attacking cells from the outside. It's now effectively sort of purified and refined within lysosomes, but they accumulate, which we have also showed in our piece of [indiscernible] neurons. So I think this is just further evidence of this shared pathology between the sort of senescent and disease retinas and brains. So thank you.

Great. And while we have you on screen here, the next question is appropriate for you. One of our viewers has asked, does reduced levels of photoreceptor outer segments in treated RPE result from reduced uptake of POS or increased POS metabolism or otherwise? So perhaps you can comment on if you have any ideas or theory to it?

Well, that's an excellent question, and I want to thank you for that. So that's a difficult one as well because the MerTK integrated mechanism, which we have also shown to occur in our highly specialist polarized RP monolayers that these experiments were done. We also know that as a function of age and disease, these processes can become impaired. So now going back to the heart of the question, is this a sort of a chicken and egg. We have no reason to believe that there is any marked change in the rate of phagocytosis or inefficient binding to skew the data to show this. Now I'm sort of comforted further by the fact that we see the same rescue effect not only through 1 disease mechanism, which is amyloid beta, which is notorious for doing exactly the kind of thing that you mentioned. So amyloid beta is quite difficult to study because it has a variety of effects from disrupting cytoskeletal movement and rearranging acting cytoskeletal [indiscernible]. So you could say, well, that could very well interfere with this [indiscernible]. But we see the same rescue effect with these Sigma-2 inhibitors using oxidative stress mechanisms. And we see the same result, which then leads me to believe that actually any effect that we may see in either reduced binding or increased phagocytosis maybe, if at all, be marginal. And therefore, I'm quite confident that what we see is, in fact, true. So that's an excellent question. Thank you.

Great. [Operator Instructions]. So perhaps this question can go to Dr. Csaky. It's similar to what we had addressed by Dr. Lim, but a little more specific here. We have a question relating to specifically whether Sigma-2 modulators are oxidative stress manipulators and how those might be viewed in context of other therapeutics, assuming that more will be approved prior to launching of this drug is approved.

Yes. I mean I think right now we're on the complement bandwagon because our therapies that we're testing in the clinic are all complement mediated. But I think the one thing that we're also finding somewhat discouraging is that the treatment effects we're seeing are really somewhat marginal. And so I think there is clearly a hunger, at least in the community, as we see these effects of these very potent anticomplement drugs being somewhat [Audio Gap] an apparent positive effect cohort in wanting to interrogate other modes of action, either as adjunct therapies or as stand-alone therapy, again, because right now the bar that appears to be set for us is still relatively low. And I think that's somewhat discouraging when we think about these patients and what their treatment burden would have to be and the ultimate effect. So I know, Jenny and I are very much involved in all of these trials and discussions, and I think there is a tremendous amount of enthusiasm for alternative mechanisms of actions, interrogating other mechanisms and taking other types of classes of drugs into the clinic.

Okay. Thanks, Karl. So today, we've heard a lot about dry AMD, about how it is a large disease, huge number of patients, and really without effective therapies. We've heard from Mary about some of the background about why we believe the therapy that we're developing for Alzheimer's disease might also be applied to dry AMD. We've heard from our experts, ophthalmologists, what's needed in the field, how this drug might fit with other therapeutics. And we've heard from Stella about some of the interesting other research that's going on and how this fits in the environment. So we are very excited to be moving forward in dry AMD. Hopefully, soon we will be able to announce when we're able to start our Phase II trial. Again, our target is to be dosing patients by the end of the year. So now I'd like to turn it over to Lisa for final comments.

Thank you, Tony. So first off, my thanks to our participants in the panel. Thank you for listening through our discussion and for your thoughtful questions. Dr. Ratnayaka, Dr. Csaky, Dr. Lim, Dr. Robertson, you have been tremendous colleagues and advisers. We appreciate your participation and your efforts helping us to advance this innovative program. To my colleagues, Mary and Tony, my thanks. We appreciate everyone's participation. This will be available on our website. And of course, we're always available to answer further questions if you reach out to us directly. So a great day, everyone, and thank you.