Good morning, everyone. Thank you for joining Unity Biotechnology's Analyst Investor Conference Call. With me today is our CEO, Anirvan Ghosh, our CMO, Jamie Dananberg, our Chief Scientific Advisor, Przemyslaw Sapieha, myself, Lynne Sullivan, the CFO. We're fortunate today to have Dr. Robert Bhisitkul, Professor of Ophthalmology and Head of the Retina Fellowship at University of California, San Francisco. Before turning the call over to Anirvan, I'd like to remind you that during today's call, we'll be making some forward-looking statements which are subject to risks and uncertainties, including those described in our latest 10-Q filed with the SEC. Actual results may materially differ from those forward-looking statements, and we don't assume any obligation or intent to update them except as required by law. With that, I'll turn the discussion to Anirvan. Thank you, Lynne, and welcome everyone who is joining here in person. We're really excited to spend the next 90 minutes or so with you, reviewing our ophthalmology program, particularly UBX1325, following the recent data that we had in DME and looking forward to readouts that are coming up in our study in AMD. I just wanted to kinda briefly cover our topics for today. I'm gonna give you an overview of Unity's therapeutic approach and our clinical development plan, and then hand it to Przemyslaw Sapieha, our Chief Scientific Advisor, who's really done foundational work in this area about senescence biology and eye disease. He's gonna review the senolytic therapeutic hypothesis with you and then share with you some recent experiments that go into the mechanism of action of BCL-xL inhibitors and how they can affect the inflammatory environment and barrier function in the retina. This is kind of foundational to the therapeutic approach. It's really quite distinct from all other approaches being explored for eye diseases, and I'm really excited to have Mike here to share some of that data with you. We'll then go to Jamie Dananberg, and Jamie is going to first review the 12- and 18-week data from the BEHOLD DME study, where we saw initial evidence of significant improvement in vision and impact on retinal structure. He'll also share with you the design of the ENVISION study, the phase 2 study in neovascular AMD. We just announced that we have added a Part B to that study that is going to allow us to learn more about the molecule, not only in a monotherapy context, but also as a potential add-on to anti-VEGF. I think through the course of that study, we'll really get a great sense of what the molecule can achieve by itself and what it might add on to anti-VEGF therapy. We'll then have Lynne come up, and she'll share with you our initial thoughts about our product strategy. We are in a space that has been dominated by anti-VEGF for a very long period of time, and so it's useful for us to start thinking about how does a new product fit into that therapeutic landscape. After that, we're all looking forward to the fireside chat with Robert Bhisitkul, and Jamie will conduct that session, following which we'll have some time for Q&A. At Unity, we are focused on developing new therapeutic approaches that would slow, halt, or reverse diseases of aging. The fundamental biology that we target is cellular senescence, and this will be a theme that will be woven throughout our presentations today, which is really quite a remarkable observation that as we age, and particularly in the context of diseases of aging, there's an accumulation of cells in our tissues that can lead to tissue damage and drive disease progression. We've been working on ways of targeting that biology for therapeutic benefit with a primary focus on ophthalmology. The fundamental biology we're targeting is also relevant for diseases in neurology, cardiology, pulmonary disease, liver disease, and oncology. In the eye, our focus is on two leading causes of blindness, diabetic macular edema and wet age-related macular degeneration. In both of these cases, these are back-of-the-eye diseases with a strong vascular component. They're progressive vision loss diseases. Over the last 10-15 years, the primary treatment paradigm has been to treat patients with anti-VEGF therapies, which has provided benefit to many, many patients. These are very successful drugs in the market. Still, even with pretty aggressive anti-VEGF therapy, a very significant fraction of patients do not achieve full restoration of vision, so they have significant visual acuity deficits. Long-term studies show that over the course of 2-3 years, many of the patients who have some benefit will eventually revert back to where they started. You're not hitting the underlying cause of the disease, and so eventually you're essentially buying some time. We are interested in developing a new class of therapeutics called senolytics, where we eliminate senescent cells in the vasculature of the eye and thereby alter the course of disease trajectory. We've been exploring this concept in a series of clinical studies. We have previously shared phase 1 data in both advanced AMD and DME patients, and that was the first time when we saw initial evidence of improvement in vision with UBX1325, our lead compound. Following that, we started two phase 2 studies, as shown over here, the BEHOLD study in DME and the ENVISION study in neovascular AMD. In the DME study, we have shared our initial 12- and 18-week data, and we'll be reviewing that today with you as well. We're very excited. We're getting quite close to getting to the 24-week data point, which is the full duration of the primary endpoints, and we have guided that we'll have that data this quarter. We've added a long-term extension to that phase, to that study, and we expect to have 48-week data in Q2 of next year, which will give us a sense of the durability and continued efficacy, potentially of UBX1325. The neovascular AMD study is about six months behind the DME study and is different in a couple of important ways. The ENVISION study is a head-to-head study of UBX1325 versus aflibercept so that we will get a real sense of, in a non-inferiority study, how patients respond to UBX1325. The initial data from that, up to 16-week data, we expect in Q1 of next year and 24-week data in Q2. We just added a part B to that study, which is the phase where we will explore the potential benefit of UBX1325 on top of anti-VEGF, and Jamie will share details of that with you shortly. Before I hand over to Mike, I just want to kind of briefly level set as to where we are and how we're thinking about where UBX1325 will play in this space. As I mentioned, in today's treatment paradigm, virtually all patients start out with an anti-VEGF treatment, and there are some patients who do respond quite well, but they still require fairly frequent injections, per protocol for aflibercept every eight weeks or so. But there's also a very sizable fraction that do not get the full benefit, and even with heavy treatment burden. The patients you'll see in our DME study really fall into that category. You'll see they have residual fluid and visual deficit. As we begin to think about UBX1325, we believe that it could provide value to both of these patient populations, and Lynne will discuss that in greater detail in her session. With that, I'd invite Mike to go over the mechanism of action work. Thank you very much, Anirvan. I'm gonna spend the next couple of minutes describing some of the foundational science behind the senescence disease hypothesis and also why we think senescent cells play critical roles in several retinal vascular diseases. Unity was founded on the concept that there is a unifying mechanism that drives diseases of aging, and that this unifying mechanism is cellular senescence. I think probably the most striking example of this is the slide that you see before you here, where these are two mice that come from the same litter, meaning they have the same mother, same father. They're born within hours of each other. Essentially, they're 24 months old, which corresponds to around 70-80 years old for a human. They're genetically modified, that when they receive a certain drug, this drug activates a gene that kills off, selectively kills off senescent cells. The mouse on the left-hand side received a placebo treatment throughout its life. The mouse on the right-hand side received this drug that activates the gene that selectively kills senescent cells. You can really see the striking difference, where the mouse on the left-hand side aged naturally. It's got many of the salient features of aging like cataracts, osteoporosis. It's got poor hair. These mice also have much higher tumor burden. Whereas the mouse on the right-hand side was protected against most of these features of aging and actually lived roughly 20% longer than the mice that didn't have their senescent cells eliminated. With this, we thought it was a strong foundation on which to build a therapeutic platform where we could, with a drug, eliminate these senescent cells. The example I showed previously was a genetically modified mouse, and now to make it more practical, we need to design drugs that can mimic what we saw in that first slide. Our understanding of cellular senescence has evolved tremendously over the last 10-20 years. We initially used to think that cellular senescence only occurred with aging, but we now know that several stressors that are actually central to diseases like diabetes can provoke or send the cell into a senescent state. What happens when age or these stressors accumulate is that there's a certain proportion of cells in a tissue that are gonna trigger a DNA damage response and essentially stop dividing or stop functioning appropriately. They're no longer gonna be able to communicate well with their environment. One of the things they do is they start to produce a very broad secretome, meaning they produce a lot of inflammatory proteins, pro-fibrotic proteins, pro-angiogenic proteins. Several of these proteins are actually targets of current standards of care, such as VEGF, for example. With the production of the secretome, you get an infiltration of immune cells, both of the innate immune system and the adaptive immune system. Essentially, if these senescent cells do not get removed or if they keep living in the tissue, we'll eventually see a fibrotic state, and the tissue will dysfunction. We've been spending a lot of time trying to understand what are the different ways that we could selectively kill these cells, and by doing so, we not only relieve the inflammation, but we also allow the neighboring cells that are still healthy to regenerate. This is, of course, a process that can be quite protracted and take a number of months to occur. Ultimately, we aim at fixing the tissue with senolytic drugs. The most fateful marker of cellular senescence is a protein called p16. This is a cell cycle regulator that essentially makes the cell arrest or prevent it from dividing. We can see that we got quite interested in ophthalmology, 'cause here you see eyes from healthy cadavers, and this is a representative OCT image, so essentially imaging the retina. You can see this nice foveal depression, whereas patients that have diabetic macular edema will have an accumulation of fluid right in this macular area. When we looked at corresponding cadaver eyes with the same type of disease, we would see that there would be an accumulation of these senescent cells, so these are the p16 positive cells, in areas that corresponded to blood vessels in these patients. With this and with a whole series of other experiments that we've ran, across different species, including mice, where we can really get a very high resolution using a technique called single-cell RNA sequencing, we were able to build this model of our understanding of what happens to a blood vessel during diabetes and where the senescent cells are located. What we found was that primarily cells called endothelial cells, so these cells that really line the inside of the blood vessel, so they're surrounded by little muscle cells called pericytes and immune cells called microglia that will actually come and fix or be part of a repair process when you have vascular damage. These innermost cells become senescent. I'll show you in the next couple of slides, some new data that we generated that suggests that once these endothelial cells become senescent, they produce their own micro inflammation and also are inefficient at, forming junctions with their neighboring cells. To try to understand what happens to a senescent cell or, an endothelial cell when it becomes senescent during diabetes, we generated this model where we would take human microvascular endothelial cells from the retina, and we would culture them for a period of around five weeks in hyperglycemic conditions. At this point, those cells would start to express markers of DNA damage. This is promyelocytic leukemia protein, so you can see these foci. This is really one of the many ways that we characterize these cells to see if they're senescent. Another one is that we look at the cell cycle arrest proteins, like I spoke before, the p16, and also other cell cycle arrest proteins called p21 and p53 that altogether give us confidence that these cells are actually senescent and that we're able to model a senescent state in a dish. As a consequence of these cells becoming senescent, we also found that they start to produce this SASP, senescence-associated secretory phenotype, with an upregulation of factors like IL-6, IL-8, and other factors that can deregulate vascular homeostasis. Once we had this model, we wanted to see what actually happened to the endothelial cells or if we mimicked having a vascular cell or vascular membranes in a dish, so essentially making artificial blood vessels in a dish. To understand how an endothelial cell holds its barrier, they express proteins on their membranes that act as a type of zipper, and they interlock between neighboring endothelial cells, and this is part of the barrier function formation. One of the most modulated proteins in diabetes that does the zippering is called VE-cadherin, so vascular endothelial cadherin, and its adaptor protein beta-catenin. They hold the endothelial cells together. When we make these endothelial cells senescent with hyperglycemia, we'd see phosphorylation of these proteins. Essentially there would be negative charges that would be given to these proteins, and that would make the cells unzipper. Here's some microscopy to see what happened once they unzippered. You can see that in red we labeled the VE-cadherin and in green we've labeled its adaptor protein beta-catenin. When we'd have these senescent cells, we'd have a lot of internalization of these transcellular zippers. The VE-cadherin and the beta-catenin would actually find itself within the cell and no longer on the cell surface. Meaning that these senescent endothelial cells are inefficient at forming physical junctions with their neighboring cells. Very consistent with the potential leak phenotype. To further gain insight on this, we made co-cultures where we took endothelial cells that were either not senescent and endothelial cells that were 100% senescent and mixed them up to get a gradient of progressively more senescent cells within a monolayer. Then we plated these on an electrode that shoots up an AC current. Essentially, this is a very standard way to measure barrier function or the amount of the capacity of a cell to maintain junctional integrity. What we found was that as we increase the amount of senescent cells, there was more and more leakiness. Essentially, the barrier was compromised. Again, giving us confidence that these senescent cells were not functioning appropriately. They were not able to form transcellular junctions, and they were not able to maintain barrier function. The idea of designing a drug that can selectively kill senescent cells comes from the idea that bad cells within a tissue can actually spread and make neighboring cells bad too. By selectively eliminating these bad senescent cells, we can confer a regenerative capacity to tissue. We spent a good number of years trying to identify selective susceptibility nodes within senescent cells, to see if we could find a way to only kill off the senescent cells and not affect any of the healthy neighboring cells. Just to summarize all this work, we came across BCL-xL as being one of these susceptibility nodes that we could target to selectively kill senescent cells. BCL-xL is a protein that's found within the mitochondria, and it sequesters pro-death proteins. Essentially, it prevents the cell from dying. With our BCL-xL inhibitors like UBX1325 and some other ones we've developed, they bind to this BCL-xL, and hence all the survival or all the pro-death proteins can no longer bind to it, and hence they migrate to the mitochondrial outer membrane, and this forms a macropore in the mitochondria. It allows factors to seep out, and this will activate cell death. It's an apoptotic cell death, which is a very clean type of cell death, so there's no collateral inflammation associated with it, and then we get elimination of senescent cells. When we looked at the expression of this BCL-xL across different models of retinal vascular disease, we often found it upregulated in areas of disease activity. Here on the left-hand side, we see that microvessels from a diabetic retina. This is a diabetic mouse retina. Again, we see that some of these microvessels really upregulate their expression of BCL-xL, and these are the blood vessels that are leaky in these mice. Now, when we looked at another model, this is a model called oxygen-induced retinopathy model. It's actually the model that was used to identify Avastin and later Lucentis as a potential treatment for neovascular AMD. We see that these pathological neovessels are very enriched in BCL-xL. Together, this gave us confidence that targeting BCL-xL in this context can potentially modify the course of disease. We went into a couple of models. The first model is a mouse model of diabetes. Here we induce diabetes chemically by using a compound called streptozotocin. What this does is that it ablates beta islet cells and so essentially the mouse becomes hyperglycemic, and within a number of weeks, it starts to develop diabetes-related phenotypes such as vascular leakage in the retina. We treat with our BCL-xL inhibitors, and at the endpoints, we can either analyze the amount of inflammation or look at vascular permeability. We did this in-house, and we also sent this out to various labs, so it was done independently verified. The conclusions of this was that with our BCL-xL inhibitors, we're able to. You see here's a non-diabetic mouse. Here's a mouse that was diabetic. When we treated with our BCL-xL inhibitors, we would systematically reduce the amount of retinal inflammation. This was measured by looking at some of the prototypical SASP factors like IL-1β, interleukin-6, and tumor necrosis factor. As a consequence of this, when we looked at the amount of vascular leakage, here I'm presenting an example of just looking at the amount of immunoglobulins that can seep out of the retina. We've also done this using an albumin based assay. What we see again is that with diabetes, we end up getting an increase in vascular leakage, whereas with the treatment, we're able to very rapidly suppress this leakage or very effectively suppress this leakage. Collectively, two things are happening here. One is that we're reducing the retinal inflammation, and the second thing is that we're actually allowing the barrier function to reestablish. We're fixing the vascular leak. Now, when we looked in our models of pre-retinal neovascularization, the oxygen-induced retinopathy model. I showed you a slide before where you saw the BCL-xL, the target of our inhibitor that was very pronouncedly upregulated in these pathological areas. These are very dense vasculature that typically grows on top of the retina. It eventually becomes fibrotic. When we treat with our BCL-xL inhibitor, we're able to selectively kill off these blood vessels. Something unexpected and pretty exciting happens is that once we eliminate these pathological blood vessels, the healthy blood vessels in the wake end up regenerating. This is illustrated here, where you see this is an animal treated with a control vehicle. You can see in red is outlined the hypoxic zone, so the zone without any blood vessels. After our treatment, we're able to regenerate functional blood vessels into that ischemic zone. The reason why this is important is 'cause these hypoxic zones are actually the ones that produce all of the VEGF or produce all of the inflammatory factors that drive the disease. We believe that this is really the beginning of a disease-modifying process, and so by regenerating a functional vascular system, we're altering the course of disease. When we put this all together, we came up with this model where essentially during diabetes or neovascularization, we'll have endothelial cellular senescence in endothelial cells. This is accompanied by an inflammatory process, so we'll get production of the senescence-associated secretory phenotype, so several of the cytokines that I spoke about in the talk. Also these cells are inefficient at forming barriers, so we'll end up having contents of the blood vessel leak out. Now, with a BCL-xL inhibitor like 1325, we're selectively eliminating these senescent cells. This is a clean process, so again, apoptotic cell death. The cell ends up getting packaged into little blebs and eliminated by the innate immune system, so it doesn't itself provoke any collateral inflammation. With this, the healthy blood vessels or healthy endothelial cells in the wake or in the neighborhood are able to regenerate. Again, this is a process that we think takes several weeks to occur. At the very end, we end up having a blood vessel that is fully repaired and able to have proper barrier function. With this, I'll pass it on to Jamie, and he'll talk about the BEHOLD and ENVISION studies. Thanks, Mike. Good morning, everybody. I would like to take you through the clinical program of UBX1325 and try to connect the dots a bit on the data that we have generated so far with the data that Mike just shared in terms of the preclinical model and what's going on. I wanna set a little context first around what we think this population of patients is experiencing. This is the data from the VISTA study, one of the 2 registration studies for aflibercept. What you can see is that it works really well in these naive patients, by the way. You'll also notice that the majority of benefit is within the first 6 months, so up to 24 weeks. Once you get to 24 weeks, you can see that there's relatively little, a letter or two over the next 18 months. If you just blow up this 24-48 week zone on the right, you'll notice that there's very little additional gain of letters. There's some, but relatively minor compared to the benefit they achieve in the first three months. It's important just to recognize that anti-VEGFs work, but they work to a certain degree, and then they're there for maintenance purposes, not really adding visual benefit to these patients. When we now look at the BEHOLD study for UBX1325, what we notice is that the protocol required that the patients had been receiving at least two injections of anti-VEGF over the preceding six months. As it turns out, the patients that were enrolled in that study had received, on average, four injections, which means patients are getting injections every four, six or eight weeks in the preceding six months coming up to this, much like the data I just showed you. Despite that, these patients still have a visual acuity deficit of at least 73 letters or worse, or 20/40 or worse, which is an important cutoff. They also have retinal fluid of at least 300 microns, and that's in spite of a fairly heavy anti-VEGF treatment burden during that period. In addition, these patients had their last anti-VEGF injection 3- 6 weeks prior to randomization. In effect, what we have, the patients who are enrolled in this study are getting regular anti-VEGF, and in and around the time they would normally get that next injection, instead, they're randomized to receive UBX1325 as a single intravitreal injection versus a sham procedure. It's worth pointing out here that the sham is exactly the same in every way to the UBX procedure, except no needle enters the eye. The hub of the syringe is actually pressed against the globe. We have previously shared 12- and 18-week data, which I'll go over with you today. Of course, we're following patients out to 24 weeks and then and then eventually out to 48 weeks. The main endpoints in this study are safety and tolerability, of course, but also BCVA, OCT structural changes, the functional changes I just described, and there's some other endpoints that we will discuss in more detail at the 24-week time point and beyond. These are the changes of the BCVA at the 12- and 18-week time points. For this population, in blue are the UBX1325-treated patients, and in gray are the patients treated with sham. What you'll notice is that the patients have this initial bump of a few letters, and then from eight weeks and beyond, this continuous improvement in visual function up to the point where they've gained 6.1 letters in addition from baseline. Remember, again, I'd point out, these are patients who have been on anti-VEGF treatment for at least 6 months and a pretty heavy burden. They are not getting additional benefit at that point. They are stabilized in terms of their visual acuity and their CST throughout. Here we're getting another more than a line of vision improvement, and that represents a full five-letter difference from what we see in the sham-treated patients. With the statistical significance that is demonstrated here, and again, I point out this is after a single injection of 1325 given four and a half months prior to the ascertainment at 18 weeks. This is the structural changes that we identified from that study, which also quite interesting, in part because there are no really strong data that tells you what happens when you take away anti-VEGF from a patient with diabetes and diabetic eye disease. We always assume that they get worse, and here's the data to demonstrate exactly that. Essentially, from two weeks on, you'll notice a nearly group mean linear rise in the fluid accumulation in these patients. Without the anti-VEGF on board, these patients continually leak more and more so that by the time you get to 18 weeks, these patients have gained over 50 microns of fluid compared to where they were at baseline on average. In contrast, the UBX patients, again, at a timeframe that matches what we see from the improvement in visual function by BCVA, stabilize that retina. Very much as like the data Mike showed, that over a period of time as the vasculature may heal itself, we see the stabilization of the retina, and you see these patients are at close to baseline throughout 18 weeks. You'll notice these two lines as the lines in the BCVA graph are still diverging by the time we get to 18 weeks. At the 18-week time point, there's a 50-micron difference between the UBX-treated patients and the sham-treated patients, and the stat sig is shown in on this particular table. We did some additional analyses as well to help us understand was there a specific patient population that drove those kind of data, and the answer is just no. When we look at a variety of baseline characteristics that essentially describe disease severity, in all cases, there was UBX1325 outperformed sham numerically in all of the different groups that we analyzed. The same was true for CST in seven out of the eight subgroups, telling us that the benefit that can be achieved from 1325 is quite broad and occurs in all baseline patient characteristics, which is really a plus for us going forward. When we evaluate rescue rates in this study, UBX had a small but clear advantage in every category of rescues. Though this is still relatively early at 12 weeks, as you saw from the data, and we're very much looking forward to the 18- and 24-week data to help us understand what happens over time to these patients. With diabetes being a relatively more chronic than acute disease, we notice in the slope of the CST line, we know that they're getting worse over time when they're treated with sham. That's something that we will test as we go forward. From a safety perspective, I just wanna point out the last line on this table. Most importantly, there was no evidence of any intraocular inflammation of any sort, nor was there any disease process associated with inflammatory changes in the eye, which is a real positive in this field. The only other area I'd point out there. It looks like there's a small difference between the UBX and sham, but of these six cases, five of them related to the needle penetrating the eye. They were mild and self-limited in a very short period of time resolving. Overall, from a safety perspective, we have full degrees of freedom to really move forward in any way that we need to. I just want to show a few slides of images, as images are often worth a thousand words here. This is a patient with DME. You can see Mike pointed out the normal OCT. You could see this foveal depression is no longer symmetric. It's asymmetric with a big shoulder on this side, mainly because of the large amount of subretinal fluid that we see beneath the retina. You'll also notice two pockets here, at least, of intraretinal fluid. If you go to four weeks in the bottom left, eight weeks in the top right, and 12 weeks in the bottom right, you'll notice the normal symmetry to the fovea is being restored. Much of that fluid subretinally has been resorbed, and all the intraretinal fluid is basically gone. There may be a tiny bit left right here. Overall, this patient lost 85 microns of fluid, and it represents a very much a positive response that we identified from this study in these patients. This is an even more dramatic case. This is a patient with clearly long-standing DME. This is a large cystic structure centrally. No foveal depression whatsoever because of this structure. I always love to point out that this patient received an anti-VEGF 3-6 weeks before this image was taken. We know that the anti-VEGF is just not doing it for a patient like this. What we see as we go to four weeks, and then at eight weeks, and then 12 weeks, the central cyst is completely gone. There's a foveal depression here that may be the first time, I'm speculating, but could be the first time in some years this patient ever had a foveal depression. You'll notice that even late, from 8-12 weeks, the intraretinal fluid deposits are still getting better over time. We're very excited to see patients like this, what happens as we get to the 18- and 24-week data in these patients from images. In summary, the BEHOLD study. What we learned is that 1325 was well-tolerated with a very favorable safety profile, no evidence of IOI. We had improved visual function that was durable through 18 weeks, and that those changes were robust across a range of baseline disease characteristics and disease severity, and that we're able to maintain, restore and maintain retinal structure even in the absence of any other treatment other than the single UBX injection. Which means that UBX1325 could be a transformative first and best-in disease therapy. I wanna take a few minutes now and just describe the phase 2 study in AMD, the ENVISION study, because we've made a recent change to that study. This is just as a reminder. Mike showed you this schematic where DME is principally a disease that impacts the retinal circulation, whereas in AMD, we're really dealing with the choroidal circulation. They're different diseases, but they're both senescence-based, and so we're very excited to explore the value that UBX1325 may have in these patients. Similarly to the VISTA study that I showed you, when you look at the registration studies for aflibercept in patients with wet AMD, the same pattern emerges. That is, the vast majority of the benefit for these patients is seen in the first 6 months. In fact, in AMD, it's probably in the first three months that the patients achieve near real stabilization. If you blow up that same 24- to 48-week zone where patients would be normally enrolled in our studies, you could see the blow up on the right. They don't even get a letter over the next six months of time. Our ability to look at the time points in here and see how well that will differentiate from ongoing aflibercept treatment is powerful. Given that, this is the design of the study. Similar to the BEHOLD study, in this particular case, these patients are also getting regular anti-VEGF injections. These patients had their last injection 4- 8 weeks prior to enrollment, and then they're randomized to receive either two consecutive injections of UBX1325 for us to be able to study the benefit or not of a second injection. In this case, we're also the control arm here is ongoing aflibercept every eight weeks. We get to make this comparison with the endpoints that are very similar to the BEHOLD study as well. Now, importantly, once we got the BEHOLD data, we realized we'd really like to see what goes on in these patients for a longer duration of time. We had the opportunity to explore a range of potential objectives of an additional add-on to this study. What we landed on based on input from informal regulatory interactions with our steering team and our broad opinion leader base, as well as statistical input into how we can evaluate these types of data, we wanted to understand the impact of a second cycle of UBX1325. Does another cycle of treatment 6 months later provide additional benefit to patients or not? What is the impact of combining 1325 with aflibercept directly? That's the design of this Part B. Part A, depicted here, is essentially the exact same as what I just showed you. We took off the sham injections here just to, for clarity purposes, but there is a concomitant sham at every place on this graph in the opposing arm. What we added was Part B, which gives patients a simultaneous injection of anti-VEGF plus UBX or a repeat cycle of 1325. This lets us compare, for example, B1- A1, to be able to understand, does the second cycle really improve things? We can also compare B2- A2. In other words, does the combination of UBX and anti-VEGF actually benefit the patient differently than just ongoing anti-VEGF? We have a lot more learning that will help us support our additional studies moving forward in terms of the future pivotal program for this molecule. This is the timeline of the program. We expect the Part B to read out, as Anirvan had mentioned, in the first quarter of next year for the 16-week analysis, and a 24-week follow-up will be in Q2 of next year. The diabetes program is ongoing, as I just said, in the BEHOLD study, and we're already in the planning process for the DME pivotal program. With that, I'd like to turn it over to Lynne to talk about the product strategy. Okay. Thanks, Jamie. I'm just gonna spend a couple of minutes talking about how we see UBX1325 possibly being used in the DME and AMD landscape. Not gonna spend a lot of time on this slide. Obviously, DME and wet AMD are very large commercial opportunities, over $12 billion currently. Different folks have different projections for 2030, somewhere between $14 billion and $16 billion over time. Currently, the U.S. market represents about $8 billion in revenue, so it's a very large opportunity in general. This slide just walks through what the epidemiology of DME currently looks like for the U.S. Right now, there's about 35 million diabetics in the U.S. Of that, 1.7 million have DME, but only 800,000 are actually diagnosed with DME, and about 330,000 patients in the U.S. are treated. It's a very small percentage of DME patients are actually getting treatment, and we think that, in fact, this could be a really large opportunity for UBX1325. In terms of epidemiology for wet AMD, very different. 11 million patients in the U.S., 1.2 have wet AMD. Of the 1.2, 1.1 actually are being treated, and mostly with anti-VEGFs. This slide shows sort of how we're thinking about the target product profile for UBX1325. It lays out three different metrics that we think are important in terms of where it would fit in the landscape and how physicians might use UBX1325. The first is durability, the next is improvement in BCVA or kind of increased efficacy, and the last is whether or not there's a potential or proof of disease modification. Does 1325 actually revascularize and improve damaged tissue? In a base case, our low case if you will, we believe that, in terms of durability, it would be four months or longer between injections and that the BCVA gain would be equivalent to an anti-VEGF, not better. We are still waiting to determine whether or not that we would see disease modification. In a better scenario, we would still have roughly four months of durability. We would have BCVA improvement that's better than the anti-VEGF. We feel like this is sort of what we saw in the 12-18-week data. You know, we got six letters above baseline in BCVA, which would fit right now in our mind to this better scenario. Again, you know, whether or not it's disease-modifying is TBD. In the best-case scenario, which we're hoping we'll get some insight at the 24-week data, do we have durability of six months or longer, which would be fantastic and sort of higher than what anybody else has shown? Also improved BCVA. Can we maintain that six letters above baseline or something better than an anti-VEGF is giving these patients on long-term treatment and whether we see evidence of revascularization. That data will come from OCTA, fluorescein angiography, things like that we haven't had yet. And when we get the individual patient data and a little bit longer than the top-line data it might take to see those visuals. Anirvan Ghosh had this slide earlier. It's sort of how we would divide the current AMD and DME landscape. There's patients that are currently treated with anti-VEGF, whether you're DME or wet AMD, and some of those patients do very well on anti-VEGF. We would call those good responders or well-treated patients. There's also a large group of patients that are sub-responders or non-responders, and so approximately 25% of wet AMD patients are sub or non-responders, and 60% of DME patients are sub or non-responders. To us, that's a very large portion of the market, and it's where we see a large opportunity for UBX1325. for patients that are being well-treated and have gotten their 8-10 letters from an anti-VEGF and they're now in a maintenance phase, if you will, we believe that there's an opportunity for physicians to want to switch patients or add UBX1325 to their regimen so that they could possibly get a bump in efficacy in terms of BCVA letters and if there's disease modification, if we can see that there's revascularization, we think that would be something that patients would also wanna be exposed to. for sub-responders and non-responders, obviously, they're not getting the efficacy that they would like to see, and I think physicians would be very willing to add UBX1325 to those patients in order to, A, improve their efficacy but also for patients that have plateaued. Again, there's an opportunity. If you can get somebody, you know, five letters, that's a line on an eye chart. Jamie mentioned before sort of this litmus test of twenty/forty vision. Roughly 40%-50% of patients that are currently being treated with anti-VEGFs don't get to 20/40 vision, which means they can't drive. If UBX1325 could be used for those patients, that's 40%-50% of the market. We do think that, you know, if we can show revascularization, if we can show improved efficacy, even beyond the durability win, we think that there's a really large opportunity here for UBX1325. With that, we are going to move to the fireside chat with Dr. Bhisitkul and Jamie. Yes, we're on. Okay, great. Okay. Hi, Bob. Thanks for joining us today. I'm very interested in having you tell us a little bit more about how you think about products like 1325 and about the diseases that we've been exploring. Just for the audience sake, I know you see patients every day and Bob is a active retinal surgeon at UCSF. First and foremost, we know that both AMD and DME has been treated with anti-VEGFs for over a decade now. They were kind of miracle drugs when they came out for sure, because there was nothing for many of these patients before. Now that we're into a decade of treatment, how important do you think new mechanisms are in the treatment of these diseases? What's the role of those drugs? Yeah. I mean, it gets to what my career has been. I've been a retina specialist now for almost 25 years. The big breakthrough came really 20 years ago. The anti-VEGF era started with Macugen, and then really Lucentis came in with the trial starting in about 2003. We're really at two decades, and you know, magnificent breakthrough. In the subsequent 20 years, we really haven't moved beyond anti-VEGF for the treatment of all of the retinal diseases, really. I have this one tool, and the tool works great in a lot of patients, and then in some patients, they have either no response or they have a partial response, which means that they're not quite resolving. Then, of course, the limitations of anti-VEGF therapy, every retina surgeon is familiar with, that there's no therapeutic endpoint. You know, we're not causing disease cessation with anti-VEGF. What we're doing is periodically mopping up the secreted factors that are expressing the disease, but the underlying disease is still ongoing. This has led the search to, you know, what's going to be the next breakthrough after the anti-VEGF era, and, you know, you've probably all seen some attempts there. For something like UBX that moves me beyond anti-VEGF, either as something that I can use in combination with that treatment or as a alternative to that treatment, you know, holds a lot of potential to help the overall population of patients with DME and AMD. Let's get into a little more specifics about that particular point, Bob. Let's first talk about DME since these are different diseases. Okay. Let's just move into the different diseases. When you think about a patient, typical patients that you see in your practice with DME, what's the trajectory these patients usually take? How do they respond to treatment? What does that look like over time? Including, you know, patients with diabetes are usually quite a bit younger, and so they're looking at decades of treatment. What does that look like in your practice? You're right. DME, you know, when you embark on it, you tell the patient that this is going to be a chronic ongoing therapy. You know, one of the jokes I use is that we will stop this therapy when you die or I die, because there's again no real therapeutic endpoint. There are patients that resolve with DME, but typically you tell these patients, "Get ready. You're going to be seeing me every month or two, maybe every three, from now on. We're gonna get to know each other." Then we've done some work looking at real world results in both DME and AMD, and this is now widely recognized. When we're actually treating patients with their real lives, their other medical problems where they miss appointments, where they get sick of the injections, you know, the long-term trajectory for these diseases, even with this, you know, fantastic anti-VEGF therapy, is not positive. They tend to dwindle down just because we have such a hard time maintaining this long-term regimen of every month or every two-month injections. Within that patient group then, which is pretty broad among the patients over time especially, what's the most important medical needs that you think should be addressed with new medicines? You know, for a new therapy, what we want is disease cessation, or disease modification. You know, let's not try to sop up the secreted factors, VEGF or other things. Let's actually go and work at the underlying disease. I think that is the sort of holy grail for both DME and for AMD. How do you think that would benefit patients? What would patients notice that would get them excited? Again, real world, real world things, okay? If you can modify the disease, maybe you are not bringing them back in year after year after year. Maybe you are not giving them an injection every month, and they're missing some of these injections, and they're dwindling down. Number one, you stop the dwindle. I have you know, we all know that anti-VEGF is great, but 30, 40, 50% of patients never reach complete dry maculas. You know, they never stop the leakage. For these non-responders or partial responders, you know, they're sort of lost to us. There's nothing we can do except keep hammering away with anti-VEGF. In the back of our minds, we know it might be futile, but there's no other tool. Give me another tool, and now I have a chance to capture that subpopulation that's not doing well with the current standard of care. When you look at the BEHOLD data, and you and I have talked about this quite a bit, what does that look like to you in terms of the benefit to patients? Yeah. Well, number one, for this sort of ambitious hypothesis of altering the cellular composition of the retinal tissue, it validates that hypothesis or at least it strongly supports it. The patient's vision got better, okay? For me as a retina surgeon, you know, these patients have already reached the plateau stage after 3, 4, 6 anti-VEGF injections. From that point, I'm only hoping with anti-VEGF therapy to prevent them from declining. Then in the BEHOLD study, to see them gain six letters, which is more than a line of vision, that's something that I sit up and pay attention to and also that will be noticeable for the patient. Again, this is in the course of their treatment where they should, at best, just be maintaining. I do think that can be a game changer for patients as well. I think Lynne mentioned it, especially in the diabetic population in DME, how many patients really just can't get to that 20/40 or better vision? Yeah, I like that endpoint, okay? With vision endpoints, there's a lot of different endpoints we can use. Gaining three lines, losing three lines, maintain and gain. Again, for the real life in a working age population, you know, these patients might be 30, 40, 50, can we keep them driving? Can we keep them working and functioning? That 20/40 cutoff is very important. It's one we should be paying attention to. If you can help me get more patients to that point, especially these ones that aren't getting there with the current standard of care, then I do think that is really beneficial for patients. I mean, you and I both have a strong focus on patients. We became physicians for a reason. I'm also interested in both from the patient perspective, but also the practicing ophthalmologist perspective in terms of the single injection or maybe two over the course of six months or a year. What would that mean to both patients and physicians, do you think? Well, we all know exhaustively this treatment burden is too much for us as physicians. It's too much for patients, and we're always trying to find ways to shortcut it, okay? Treat and extend is the current one. Retina surgeons are trying to find the way to give the least injections, even though it may go against our practice economics. You know, still for the benefit of the patients and just for ourselves to stay sane and for the patients not to fall out of our practices, we are trying to reduce the number of injections. Mm. Durability is very important for us. Again, I think with UBX, the durability is not the same as other drugs that are aiming to increase durability of, say, anti-VEGF therapy, where, you know, the drug or at least the effect of the drug is lasting for three months or four months. Here again, if we're modifying the disease, the durability is a different concept. You know, if this disease modification can get me out to four months or six months of changing the cellular composition, that's really remarkable above just having a formulation that lasts for three or four months in the eye. That's awesome, Bob. You've seen the BEHOLD data up to 18 weeks. We have the 24-week data coming. What from what you've seen so far, as you think about it, how do you think it would be first used? How would it be applied in most practices? What's your thought- Yeah With these kind of data, how would it get picked up? I mean, we're retina specialists. Put it in our hands, and we are going to try all kinds of things with it, okay? We're not necessarily going to stick to the rules. At first, I think there will be this sort of adaptation that follows the strict guidelines. Once it's out there in the community, then we're gonna take over, and we're gonna learn how early can we intervene in the disease process, okay? Do we use this as a combination? Do we use this as an initiation therapy? You know, for me, a treatment that you give as a single injection or as two monthly injections and then you sit back because you've altered the retinal composition, you know, to me that's. I might be speculating a little bit here, but why wouldn't I use that as an initiation therapy and then continue with standard of care or maybe withhold standard of care and see how the patient does? Anyway, get it out there for the retina people, and we're gonna run with it. Let's shift to AMD. Okay. It's different disease, and these are older patients, but a more aggressive acute disease, I think is a good way to think about it. Not really 1325 related specifically, but what is the typical trajectory of most AMD patients? Yeah. I mean, it's a more blinding disease. As you said, it's more acute. You know, a 65-year-old or 70-year-old will come in, and they're losing vision over a week, and they'll be blind in a month without treatment. So a more severe disease. Again, we're buying into a ongoing treatment and AMD even more so than DME. There's very few cases of disease resolution and treatment cessation, so it's something that I'm gonna be giving the patient probably for the rest of their lives. In that case, how is a potentially disease-modifying treatment in AMD, how important would that be then in your view? Yeah, huge. I mean, we know with anti-VEGF, we're stopping the CNV from leaking, but we're not eliminating the CNV. The CNV may even actually be growing while we're stopping those vessels from leaking. We're not stopping the underlying disease process. Whatever inflammatory mechanisms are going on, they're still going on. Give me something that sort of rejuvenates the retina. Give me something that causes those, as Przemyslaw Sapieha showed, give me something that causes those CNV vessels to selectively undergo apoptosis. Mm. I think it can change the long-term course of this disease. Especially, remember, because we're always to some degree gonna be failing with macular degeneration therapy in the real world. We're not gonna give it enough. The patient's not gonna come in enough. If you can give me something that gives me more slack, so to speak, you fix the disease so I don't have to give such a strict treatment regimen, I really think it changes the outcomes for AMD a lot. In the Part B of our study, we're adding on a combination to be given simultaneously with an anti-VEGF. First of all, how easy is that to do? Second of all, how interested are you and physicians in general with the possibility of combination treatment? Yeah. Well, two things on the combination therapy. First, you know, we've had some combination therapy trials, okay? In some ways, we've been a sigh of relief that they haven't worked because some of these combination therapies where you're giving drug X every month and you're giving Eylea every month, you're talking about 24 injections per year, okay? Maybe you're treating both eyes. You're talking about 48 injections per year. Call it 40 injections a year. That treatment burden is really going to be very difficult for us. So combination therapy, in general, gets a groan from the retinal community, but we gotta think differently with something like UBX. UBX might be a one and done, or it might be a once every six months. So I'm not really doing a combination therapy where I'm giving the patient double injections when they come into my clinic. I'm gonna give them a front-loading treatment with UBX, and then I'm gonna continue standard of care, so it's a different type of combination therapy that's gonna be much more palatable to us and doable. Particularly if the standard of care trajectory changes as well. Yes. Maybe I don't have to give monthly Eylea, you know, or faricimab or whatever I'm doing. For the most part, I think you alluded to this when we were talking about DME a little bit. In general, we focused on in our clinical studies to date patients who've been on anti-VEGFs and are, you know, it's just not quite doing it for them. They still have functional deficits. They still have fluid. What do you think the path is to looking at earlier patients? I think you alluded to it, but maybe a little more explicitly to getting to earlier patients, even naive patients. Yeah. I think that'll happen. I think that should be tested in the phase 3 trial. I think DME naive DME patients should be included in that trial. Again, put it in our hands, and we're gonna try different things with it, including in studies and things like that. For, again, for a one and done treatment or for a treatment that's rejuvenating the retina, maybe I use it in patients before they reach the stage where they would require sort of the acute therapy with anti-VEGF. I can intervene earlier with DME. You know, this is getting into blue sky things, but maybe I reverse their retinopathy so that they never reach the stage of DME. Maybe I give patients who have already lost one eye with AMD, I treat the other eye at the first sign because we know there's subclinical CNV that occurs as well. Again, put it in our hands, and we'll learn how to use it earlier. We'll learn how to use it as combination. We'll learn how to use it as a switch therapy, maybe even as a monotherapy for a certain subpopulation of patients. The last question I have for you, Bob, is something Mike shared a bit about that we are still working to generate the data on, so this is still speculation. Can you talk a little bit about the role that ischemia may play in both of these diseases? Right. I mean, these. They're multifactorial diseases, both of them. Let's just start with the case of diabetic macular ischemia. You know, patients can go blind from diabetes a few ways. One is with fluid in the retina. The other is just they lose that capillary perfusion, especially to the center of the fovea. You know, we call that macular ischemia, and right now that's a totally unmet need. We know once they develop macular ischemia that there's no hope to restore vision. If you can prevent that, if you can reverse it, then you know you really have a revolutionary treatment. You know, that's gonna be a harder endpoint to show in all of these studies. At least from the scientific work, it's a potential mechanism. In AMD? In AMD, very similar. Can you rejuvenate the choroidal vasculature so it doesn't develop the oxygen deprivation that stimulates the CNV? Again, earlier intervention that either prevents the disease or decreases the severity of the disease. That was great, Bob. Thank you so much for some of your insights. I think we have a lot of people here who might have some questions, so we're just gonna bring the crew back, move some chairs over, and then we'll get to your questions. If Mike and Lynne can come forward. We'll open it up for Q&A now and as soon as Bob is seated. Bob, thanks again for that insight and your guidance in helping us think about the program. There's a mic, so we could go to Salim. Thank you for all the color, guys. Appreciate it. Salim Syed, Mizuho. I guess three questions for me, if I can. You guys spoke a little bit about how you're now thinking about combination therapy for AMD, and you've had some informal interaction with the regulatory authorities. Just curious what sort of interaction you've had on the DME side combination therapy, or if you're using the AMD data to first inform the combinations, potential combination arm in either a phase two or in the pivotal phase three for DME. Yeah. Maybe, Jamie, you can comment a little bit about what informed that design. Yeah. The simple answer to the question is, the FDA typically doesn't distinguish from a safety perspective between the two diseases. They have given us feedback that if it's safe in one, it's fine in the other domain. We've been given a green light to proceed with the dual injection, have submitted that amendment of the protocol already, and no issues so far. For DME? We've not submitted that for DME yet. We've submitted for the AMD study, ENVISION. From the feedback we've had, there's no distinction between the diseases. From my perspective, we have a green light to be able to do whatever we need to do in both diseases. Okay. Just on the AMD piece here. Dr. Bhisitkul, I'm curious to get your view on the clinical meaningfulness and what you would expect to see in the BCVA change in the combination therapy, given this is a more severe, as you put it, manifestation of this disease. Does it differ at all from DME in how you're thinking about clinical meaningfulness in the combination? Salim, the question in AMD In AMD. with the combination. In the ENVISION. Yeah. You know, AMD is a more acute disease, so I'm sure in your discussions with Wiley Chambers and the FDA, it wasn't an option to withhold anti-VEGF in this population. They're getting the anti-VEGF in the treatment arm and UBX as a head-to-head comparison. In the combination arm, of course, what you wanna see is superiority, right? That's the justification for combination of both of them. In the combination arm, you'll be looking for superiority of UBX plus Eylea over Eylea. In the head-to-head comparison, you'll be looking for non-inferiority. Okay. Just lastly, my understanding is Part B is in the AMD study is currently blinded, correct? Just curious if you guys will be taking any looks at the blinded aggregated data at all, if that's any possibility to potentially think about your strategic. Yeah. part for the success Yeah, comment on overall. The design, the other studies is gonna be masked throughout, including in the Part B phase, right? The study will continue, you know, from Part A into Part B, and physicians, patients will not know what arm, you know, a patient is on. As of now, we have plans to analyze the data at 16 weeks and 24 weeks for the AMD data as we have mentioned. I think, you know, beyond 24, when we go to the Part B phase, one thing we have not finalized yet is whether between 24 and 48 there's any additional analysis that we do. We'll share with you as soon as that's clear. Would that be on a blinded basis, you think? Or you would unblind? No, it would be in a masked assessment the way- In a masked the way we did the 12 and 18. Yeah, just for Yeah For clarity, Salim, we'll keep the patient level masked. The group level, we unmask. That's how you release the data. We share the group mean data, so we can see that. But we don't go details into the patient level. Probably we, again, as Anirvan said, we haven't finalized that piece for Part B yet, but more likely we'll keep that masked completely, at the patient level all the way through because we have a new—we've instituted a new treatment modality, and we wanna really study that. In the BEHOLD study, we will be unmasking at the patient level for us, but the patient and the sites will still be masked for the latter half of the BEHOLD study. Okay. Okay, great. Thanks so much. Thanks, Yigal. Hi. Thanks. I had a question for Dr. Bhisitkul about the potential design for phase three for DME. In the phase two, they did the active 1325 versus the sham. I'm just wondering for phase three, what you would suggest in terms of a design. You could imagine doing non-inferiority versus the active anti-VEGF and proving non-inferiority, but much less injection burden with 1325, with the potential as well for superiority on vision if you see that. Just curious if you think that's the right way to go, if there's another avenue for the phase three. Yeah, Yigal, these will be the big decisions to make with the company of how to design that phase 3. Unlimited money, unlimited patient population, wouldn't it be nice to have all arms, okay? UBX monotherapy with rescue, of course. UBX plus anti-VEGF versus anti-VEGF. You answer a lot of questions. One of those comparisons has to be a superiority comparison, the other is a non-inferiority comparison. Again, non-inferiority with one treatment up front, okay, for six months or maybe longer, really will be convincing to the retina community that this is the way to go. More likely in the real world, as said, we would use that and then supplement with anti-VEGF therapy. Perfect world, you'd have all three arms. My other question is going back to Mike, what Mike was talking about with the senescence-associated phenotype and the evidence of senescent cell death. I mean, at this point, we've seen some of the early clinical data for DME. Do you care at this point whether we actually can show the senescent cell death manifest in human retinas or the downregulation of BCL-xL? Or at this point it's, you know, the clinical data has proven the mechanism, we don't need to go back to look at that. Yeah, hard to do. Okay. I mean, ideally, we'd find a way to show that sick endothelial cells are gone and they're replaced by healthy endothelial cells. At least now for in vivo imaging studies, we don't have any way to do that. There's some markers that you can look at. We're thinking about some of those now, and this would be in terms of decreased ischemic areas, decreased non-perfusion. That would be a strong indication, okay? If you could look at blood flow rates, okay, with things like Doppler ultrasound, where we can look at blood flow, or OCTA now is very good at looking at red blood cell speed within vessels. They could be pretty good biomarkers to show that this is the schematic that Mike Sapega L has shown is actually validated. The bigger picture for me is, again, this was an ambitious hypothetical mechanism, very ambitious. We're gonna get rid of the sick cells, and they're gonna be replaced by healthy cells. The fact that if it's borne out to 24 weeks that the patients are having this six-letter gain, then that in itself is to me, very strong support for this mechanism, even in the absence of histopathologic data that shows that the sick endothelial cells are not inside the blood vessels more. Does that get to the answer? Oh, yeah. Thanks. Thank you. Thanks, Yigal. Brandon Wagner. Hi, Brandon Folkes from Cantor Fitzgerald. Maybe also for Dr. Bhisitkul. Just following on from that, how important is disease modification for you in terms of. You talked about a lot of potential uses of the product, but if we hit on durability and improvement in BCVA, does that change how you may use the product? Yeah. I mean, it's a key question here because it's, you know, to use an overused term, it's a paradigm shift. It took me a while to get my head around this because I'm so used to there's a sick cell, it's gonna stay sick, but it's releasing this factor that I can now block and control the phenotype of the disease. Now we're gonna replace the sick cell with a healthy cell, so I gotta change the way I'm thinking there. This disease modification I do think is going to both change the patient management trajectory, and it is also going to change the way I think about when I can intervene. Okay. If I have a very early-stage DME patient, do I really wanna jump onto the wagon of giving them monthly anti-VEGF injections when their vision is still pretty good, or do I wanna wait until they've started to decline, and then I can justify this heavy treatment burden? That's how the anti-VEGF world is right now, and I have this discussion every day. We won't start treating you yet. We'll wait and see. If I have something that I can give once or twice or infrequently that modifies the disease, then me and the patient are much more motivated to initiate this therapy. It's easier to undergo the therapy, and it might have more benefits to actually come in at an earlier stage. One follow-up, if I may. You know, given the potential, I think you used the word one and done, and granted you're not a payer, but I do wanna just jump ahead. How do you think payers are gonna look at, you know, where this needs to be priced to have the flexibility you're talking about? I'll start here, and then we'll see what we can say. You know, Brandon, I think that the primary focus is to develop a, you know, new therapy, new drug that clearly provides benefit above what they give with anti-VEGF, right? I think we heard a lot about kinda what those dimensions could look like. I do think this efficacy gain, potentially above what they are getting with anti-VEGF, is a huge value driver. You know, we were at AAO just the other day, and I think that you see a fair bit of work on can you get patients to every three months or every four-month treatment with some kind of anti-VEGF variant, but none of those things give you additional letters. For us, I think the focus is to generate the data that says we are gonna improve your vision above what you can get in anti-VEGF. I think we're quite confident that with that kind of efficacy, that we'll have the right kind of reimbursement model. All right. Are there any questions additionally? There's one at the front. Hi. Thanks for taking my question. Rudy from SVB Securities. I actually have a question for the upcoming data, the 24-week data. For now, like for the 18-week data, we see like five letters of gain versus sham. I guess my question is like for the 24-week data, like what's the bar like for BCVA are you looking for or do you feel more comfortable going forward? I also have a question for the doctor, like in practice. I guess my question is like what's the bar that you're looking for if you wanna switch patient from VEGF to this new mechanism products? Or what's the bar like when you wanna add these products, like as a combination? Okay. Maybe I'll start off and then Bob you can add. You know, for us in that first study, what was really critical is to see whether or not there's any evidence of any improvement in letter gain compared to what they had with anti-VEGF. I know, Bob, we talked about it before the data, and you thought it'd be quite remarkable if you got a, you know, one or two letters even. I think that we, you know, that separation for us is really critical and you'll recall even at 18 weeks we don't have the we didn't have the full 18-week data. We had the majority of patients at 18. For us, it's very important to first of all validate that with the full 18-week we see that 5-letter separation. I think it's a very important question to ask, do you see that maintained through 2024? It's easy in your mind to draw a line saying, "Oh, it's." That's another several weeks. With any treatment we expect at some point the effect begins to wane. In our case, I think understanding that will help inform what the next study would need to be and what a treatment paradigm might look like. You know, for example, are we looking at a future where we are treating patients every six months or is it every four months? I think the data clearly shows that we can get to four and a half months with very strong results. I think if we can get to six, that would be really quite incredible. You know, we'll continue to follow them beyond that because what I don't know, and we've talked a lot, we're all learning at the same time here, is that if there's some kind of a switch mechanism that really gives you pretty long, sustained benefit. I think, Bob, you can maybe speak to, you know, what these levels of letter gains mean and is there some threshold of gain where you begin to see that this is valuable? Well, statistical significance, number one. Okay? Even if it's a letter or two, it's validating the drug for me, and it makes it viable for me to use it. We've always argued about what's clinically meaningful, and we've always set that threshold around three letters. Okay? So six letters, you know, you're really again, in this plateau stage, you're really changing, if it's borne out. Mm-hmm You're really changing the course for patients. The second question was either using this as a switch drug or adding it in as a combination drug. The clinical trials are going to help us inform us for that. Again, put it in our hands, and we're going to try different things with it. As I said. The switch mechanism will probably be that 30%-40% of patients who are poor responders to anti-VEGF monotherapy. Then we might say, "Okay, let's stop the Eylea. We've been doing it for six, 10 injections. Let's switch over to UBX and see how they do with no treatment." I already know that the anti-VEGF is not doing much for them, so I withhold the anti-VEGF and switch. The others is that patients that maybe are responding, but partially, do I add in the UBX1325, okay? Then still continue standard of care. The patients that I've got under control, but I have to give them Eylea every month, every two months without any letup. Can I add in the UBX1325, continue the standard of care anti-VEGF, but maybe now try to extend the time between the injections of the anti-VEGF, more while. This is very important, while keeping the same or better visual outcomes. Thanks, Bob. Are there any questions? Go ahead, Vivek. I just have a quick follow-up on that. That's an interesting point. Sorry. That's an interesting point you made in terms of potentially layering in the 1325 and then attenuating the anti-VEGFs. But in order to do that, I mean, your goal is to reduce the injection burden, so you would have to do it such that overall you would bring down the total number of injections by adding 1325 and taking off the anti-VEGF. Is that a fair statement? In a clinical trial, yes. In the real world, what I'll do is they're on monthly Eylea, and I've tried to extend them to two months or three months, and it's failed. Okay. I'll put on the UBX, then I will again go through that treat-and-extend process with the Eylea, and maybe now I'm successful at two months or three months, and at some point I get brave enough to withhold the Eylea and treat them quote PRN and bring them back and see if they need it. Okay. Does that answer it? Yeah. Okay. You know, I think it's worth emphasizing that, you know, if it's strictly a durability play, then what you said exactly holds, right? Which is to say that your vision will be the same as anti-VEGF, and then the net frequency ought not to increase compared to what you're getting. I think if there's a vision gain on top of it, then this question about like, you know, how frequently you treat is probably back in discussion again, right? Because we don't know how often that's gonna be, but I do think the efficacy axis is gonna be an important element. Vision is first and foremost. Yeah. Reducing the number of injections is a secondary. Jamie, do you want to add something? Yeah, just one thing to keep in mind. If what Bob suggested plays out, patients on every month anti-VEGF, and you give them UBX, the fascinating part is it clearly underscores and demonstrates the disease modification that's going on because the UBX is gone in a couple of weeks. It's not there one month later, two months later, three months later to support the retina. It's gone. You've done something fundamental to the retina to allow that extension to occur. If that were to happen, I think it's very self-reinforcing of the value of a product like this, which can really change the pathophysiology and physiology of the retina itself. Are there any questions that you have online that have not been addressed maybe? Yes. This question comes from Andreas at Wedbush. It's four parts. The first part, can you provide more details on the characteristics of the subgroups that showed benefit in BEHOLD? Sure. Go for it, Jamie. There were four different factors, the BCVA, the CST, the DRSS score, so degree of retinopathy, and hemoglobin A1C, so degree of diabetic control. Basically, we saw an even distribution of benefit from whether a patient had better or worse BCVA at baseline, better or worse CST from baseline, better or worse retinopathy at baseline. It was a broad benefit across all patient populations for both BCVA and CST. Can you share more thoughts on how the MOA explains the pronounced effect on BCVA and CST after 8 weeks? Okay. There's a two-parter here maybe. I'm gonna, I'll set it up, and then I think, Mike, you can elaborate. You know, it's important to note that, you know, one of the things we have seen and you all saw is that it takes some time for the effect to kick in, as it were. Like, you know, we're learning this, you see that, you know, there's a period of about three weeks when the effect on BCVA starts increasing. That is actually also quite coincident with when you start seeing the effect on retinal structure, right? The separations happen at about the same time course. That really, you know, reinforces our conviction that these mechanisms are linked. It's something that's happening in the retina and BCVA. Mike, maybe you can just reinforce kind of the steps that you envision would be happening during those 8 weeks that might account for the effects. Yeah. Absolutely. Exactly what Anirvan said, and just maybe to add a bit of what we think is happening. We know, as Jamie pointed out, the drug is gone within days. At that point, we think that the sick endothelial cells have started dying out. You very rapidly have a local immune response, which is microglia cells. They come and patch up holes that might be left with. Not holes, but essentially once the endothelial cell dies out, you have a microglial cell that patches it, and it's really a regenerative process. If you're to grow blood vessels in a dish, if you try to make a retina from iPSC cells, it takes nine months. It's essentially a very protracted process. We think that it gets triggered very quickly, then it's really a reparative process that takes, in our case, looks like two months. Yeah. With the updated design to ENVISION, are you thinking of UBX1325 as more of a combination in AMD and monotherapy in DME? Yeah, I can address this. No, at this point, we're really trying to understand where 1325 would have most value in AMD patients and in our overall design of the ENVISION study is meant to address that. In part A of the study, I think we'll get a good sense of what does monotherapy 1325 achieve compared to head-to-head of aflibercept. In part B, we will assess whether now on those patients that have been on aflibercept for several months, now if I add 1325, do I have added benefit? I expect that at the end of this period, we'll have a really good sense is that is it primarily working more effectively as a monotherapy or in combination that will influence our design of future studies. Lastly, would improvement or maintenance in BCVA and CST, even if rescues are reported as one or two rescue injections, be a win in the 24-week data, DME data? Yeah. I mean, for us, I think that if you see anything, you know, that we saw in 18 weeks and that pattern continued 24, that would be a huge win because that, then you have patients going six months and getting significant letter gains, and we're just waiting to see what happens. How should we think of read-through from DME results to AMD? There are a few reasons to believe that the molecule, the mechanism could also work in AMD, and I'll just summarize some of them. From preclinical models, we know that in models of neovascularization, targeting BCL-xL, as Mike shared with you, has a significant impact on vascular health, so that we have kind of the biological underpinnings of it acting in AMD. Historically, drugs that have worked in DME have also worked in AMD, most likely because they share a certain vascular pathophysiology. Based on that, we would expect that the likelihood of AMD does go up, of seeing effect on AMD goes up if we see an effect in DME. Do you want to add something? Just the phase one data. We also saw a benefit among the AMD patients that were enrolled in that study, even though those were very late patients who were no longer on any anti-VEGF treatment, which tells you how late they are in the disease, and yet we still saw some letter gains in those patients. Stabilization of the retina as well. We're encouraged by the phase one data as well. That's good. We'll probably take one more. We're just about out of time, I think. How large does a study need to be in terms of N to gain confidence around its clinical profile? Well, I think Bob mentioned this. I think that the you know, the study needs to be sized so that you can show statistical significance and a convincing evidence and efficacy. I think what we have seen so far, the 18-week data kind of hits that bar. You know, strong statistical significance at 18. That is the way that it would need to be sized. I think once we have the full view, let's say at the 24-week data point, that will clearly influence how big the next study would need to be based on the kind of effect size that we are seeing. Is there another burning question? Okay, we'll take one more. Does adding part B to the ENVISION study affect your runway? And when should we expect AMD data? Lynne, do you want to comment if it has an effect on runway, adding the part B? Uh- Maybe you can remind them what the runway is and. Yeah, it does, but we've taken it into consideration. Our runway since we did the follow-on is now into 2024, which is greatly extended from through Q1 of 2023. In getting to that runway, we've taken the cost of the Part B study into account. All right. Thanks, Lynne. I think we'll wrap up here. Again, thank you everyone for being here in person or joining us online. At this point, we'll close this part of the program. For those of you who are here, I'll just say that, you know, we have the opportunity for many of you to meet with us and with Dr. Bhisitkul over the next couple of hours. You're free to work in this room or the room right next door. There's food and drink. Make yourself comfortable. The room where we'll be meeting is the boardroom that is right across from where we had breakfast. If our team could migrate there, but we'll start that part in about 10 minutes. Thank you all again for being here.