Good morning, and welcome to the Unity Biotechnology Ophthalmology Day. I'm Anirvan Ghosh, CEO of Unity. It's great to see all of you here, and welcome to everybody who's joining online. This is an exciting time for Unity. We're just about a little over a quarter away from having twenty-four-week data on our study of UBX1325, head-to-head being evaluated against aflibercept in patients with DME. Over the course of today's program, I want to give you a sense of what drives our excitement, what the fundamental biologies that we are targeting, unmet need in DME, and our clinical development program. Before I get into the program, I want to make a note that during today's presentations, we're gonna be making a number of forward-looking statements. I encourage you to review our SEC filings, including our latest 10-K filings, for a complete description on the status and the business associated with Unity. Today, we're joined by a number of retina specialists. We have Bob Bhisitkul here, professor at UC San Francisco and a senior clinical advisor for us, who's gonna review with us the BEHOLD data set. Later on in the program, we'll have two retina experts, Doctors Arshad Khanani and Dante Pieramici, who will lead us through a discussion about the unmet need in DME and where a molecule such as UBX1325 could become into play in clinical practice. Just to review our program for today, I'm gonna start out by giving you an overview of Unity and our pipeline, after which I'll hand it to Alicia Tozier, our Chief Strategy Officer. Alicia is going to review with you the unmet need in DME and where we see a new mechanism of action could have an impact. After that, we'll move to Mike Sapieha, our Chief Scientist. Mike is going to talk to the, you know, key preclinical evidence about the potential benefit of a Senolytic drug. I think it's one of the most exciting biologies that I've seen in a long time, so you'll get a taste of that. And that has really been the motivation for us to move this program to the clinic. As you know, for the last couple of years, we've been advancing it through subsequent clinical studies. Dr. Bhisitkul will review with us the clinical development program, and in particular, the highlights from the phase 2 BEHOLD study, which is the first study where we really started seeing an impact on vision in patients with DME for whom the standard of care was inadequate. I'll come back and review with you our current study, the ASPIRE phase II-B study, and also very recently, we had a productive interaction with the FDA. So I'm gonna tell you a little bit about that interaction and how that is shaping our thinking around a potential pivotal study. So there's a lot coming up. Finally, Alicia will be back here to lead us in the fireside chat with Doctors Khanani and Pieramici. At Unity, I'm joined by an exceptional leadership team, many of whom are here today. Lynne Sullivan is our Chief Financial Officer. Lynne was formerly SVP of finance at Biogen. Our Chief Legal Officer is Alex Nguyen, who was previously at Roivant. The most recent addition to our leadership team is Alicia Tozier, who's right here in front. Alicia brings deep expertise and experience in product strategy and commercial strategy from her time at Genentech and Astellas, and is really helping us think through about what the next study would need to look like to create a product that is really valuable in this space. I mentioned Mike Sapieha, who's our Chief Scientist. Mike is a distinguished investigator and professor at University of Montreal. Has really been working with Unity even before I was there and has done seminal work in the field, particularly with regard to the senescence biology hypothesis for retinal disease. And finally, Dr. Bhisitkul is our senior clinical advisor and has been involved with the company and with the program from its inception. We're developing a new class of therapeutics called Senolytics that we are targeting, that we're applying initially towards ophthalmic indications. The lead indication is diabetic macular edema. DME is a progressive disease of vision loss, and if inadequately treated, eventually leads to blindness. And it's really devastating for patients who have it. They can't drive after some point. And a very significant fraction of the patient population is... it does not benefit optimally from the current standards of care. So we see this as an area of big unmet need and an opportunity for UBX. As you know, diabetes is on the rise, and along with it, diabetic macular edema continues to rise globally. The biology we're targeting is also relevant for other retinal diseases, including diabetic retinopathy. In today's presentation, you'll see some new data actually that comes from the BEHOLD study that speaks to the potential impact on diabetic retinopathy. Bob will review that with us. And geographic atrophy being a different retinal disease, where there are very few treatment options, but we see the same signature of disease with regard to senescence biology playing a role, for which senolytics could provide therapeutic value. For the past couple of years, we have been advancing our lead program, UBX1325, in retinal eye diseases, and this just provides you a snapshot of some of the kind of key milestones. I'll just start by saying that it is useful to remember that the way we're targeting disease is really fundamentally and very, very different from everything that is being tried in this field. For retinal eye diseases and for DME, the standard of care for over a decade has been anti-VEGF treatment, and this is a burdensome treatment. People come in for an intravitreal injection every other month, and it does not slow down progression of disease, so the senolytic mechanism of action, the idea is that we might be able to change the fundamental biology that drives disease, and therefore alter disease trajectory and disease progression. All the evidence that we have pre-clinically and the clinical data support this possibility. Perhaps most importantly, were results from our phase II BEHOLD study, which you'll hear about later today, where we found that in patients who had plateaued on their anti-VEGF response and still had residual visual deficit, when we switched them and gave them a single injection of UBX1325, we saw a significant and sustained improvement in vision that lasted all the way through a year, which is pretty remarkable when you think about it. Based on that, we initiated our phase II-B ASPIRE study, which is our current ongoing study, and this study is designed as a head-to-head study against aflibercept, the current standard of care. It's a medicine that is very widely used, and anti-VEGF has been the mechanism around which new products are mainly being developed. So for us, these upcoming readouts in ASPIRE are really critical, and I think will shape exactly where UBX1325 might provide benefit. We recently had an FDA interaction where we explored various elements of what a potential pivotal would look like, and I'll just touch at a high level on that feedback. I'll just say here that our expectations on our pivotal were largely in line with their expectations, and we expect that study to largely keep the key elements of the ASPIRE study into the pivotal study, which reduces the risk from going from a phase II to a phase III study. Finally, just note that we're fairly close to data, as I mentioned, expecting both twenty-four-week and thirty-six-week data early in the first half of next year. Let me just spend a minute talking about how UBX1325 could be differentiated from the current standard of care, so whenever you're developing a new drug, you have to be mindful of: How are patients being treated now? And where are the opportunities for differentiation? How do you bring a better product to market? The standard of care is anti-VEGF, especially aflibercept, and a recent entry into this field is faricimab, which is also largely based on VEGF targeting, but additionally also targets Ang2 as a second mechanism. There are a number of places where we believe UBX1325 could provide differentiated benefit. I'll start out on the patient population. As I mentioned, and you'll hear from Alicia, there is a significant fraction of patients who don't get optimal benefit from an anti-VEGF, so the question is: What do you do with them? And when the only treatment option you have is an anti-VEGF therapy, you switch them between different anti-VEGFs. So to I think to break that cycle, you have to have a new mechanism of action. In our case, we believe UBX1325 could provide that opportunity to provide benefit, especially to patients who are receiving suboptimal benefit from the current standard of care. Durability is key in this field. Aflibercept standard dosing is one injection intravitreally every other month. A lot of patients need more frequent injections. You'll see in the BEHOLD population from our data and our study that they needed an injection every six weeks or so. So they're heavily treated patients. From the BEHOLD study and the mechanism of action, we believe we can take patients a much longer duration before we need to retreat them, and our aspiration is to have a treatment that can be a twice-a-year treatment. Finally, there's an aspect of biology that I think is very exciting. I mentioned that anti-VEGFs do not really change disease progression, whereas in preclinical models, what we see is that by targeting senescent cells and changing the factors that drive disease progression, that eventually we see healthy vascular growth into ischemic areas of the eye. It's a big problem in DME. Once you have an ischemic area, nothing can be done. Essentially, you lose vision from that part of the eye. And so the ability to restore vasculature into those areas could provide the opportunity for disease modification, which I think is very exciting. We've been exploring UBX1325 in a number of clinical studies. Last year, we shared data from the BEHOLD phase II study, and we initiated the ASPIRE phase II-B study. As I mentioned, and we announced it earlier this year, we have completed enrollment in that study. There has been very high patient and investigator engagement. Many of the investigators from BEHOLD are investigators in ASPIRE, and we are on track to have twenty-four-week data in Q1 of next year and thirty-six-week data in Q2. While our focus is on UBX1325, at Unity, we continue to explore other mechanisms of action that could also provide benefit or target elements of biology that are involved in disease. I'll just note here that another pathway that is linked to vascular integrity and potentially very important in eye diseases is the Tie2 pathway. We have a VEGF/Tie2 bispecific program that is at the GLP tox stage that has very promising preclinical data. We also had a program in neurology that provided alpha klotho as a cognitive-enhancing molecule, and we spun out a molecule of a company called Jocasta, and Jocasta is developing Klotho in cognitive dysfunction. So with that, I'm going to invite Alicia to come up here and share with you, give you an overview of DME and the unmet need. Alicia? ... Thank you, Anirvan. So as Anirvan mentioned, today we're going to walk a little bit through the science behind UBX1325. We're going to spend some time on the current data to date and what's on the horizon. But before we do that, we wanted to spend a moment just to talk about why this matters to patients, to physicians. And so as we look at the DME market size, you can see that there's over 30 million patients worldwide, 1.7 in the US, and roughly 700,000 patients diagnosed and treated within the US. And let's not forget that when we're talking about patients, a third of these patients have bilateral disease. In other words, they're affected in both eyes. And as we think about this market, which is growing day- by- day, what we wanted to pause and reflect upon are the current dynamics, three of which referenced to the right, that patients are dealing with as they try to manage the disease today. As you look across the top, you can see that some patients will get a response, but maybe not as adequate as we would hope. The second is a scenario where patients may get that vision initially, but we start to see that decline over time. And last but not least, there are patients who have a significant treatment burden, which leads to them discontinuing therapy altogether. And so what we've captured here essentially is not data from within Unity, but data from the community that has called out this need. As we start at the top with an inadequate response to anti-VEGF therapy, what we may not all know is that half of patients actually achieve a suboptimal response. A third may not respond to the molecule at all, and a third of patients are still requiring monthly dosing. anti-VEGF has been a game changer in this market for the past 18 years, and clearly, there are patients who need a little bit more. The second category is looking at patients who may actually, fortunately, achieve vision in the beginning. What we know is after the one-year marker, that can continue to decline year- over- year through year five or beyond. A third of those patients, by year four, don't have that 20/40 vision required to drive. Let's not forget, these are patients that are working age, so this is absolutely critical. The last data point, which is worth us pausing and reflecting upon, is referencing the IRIS database, which we know is quite reputable. A recent analysis as of this year looked at that patient population and found that half of patients will discontinue therapy after six months. Clearly, there's an unmet need. What does this all mean? Essentially, this is why companies like Unity and others are bringing new MOAs to market, trying to find a need to address these patients. On the next slide, we captured just the top three unmet needs, that we believe UBX would be able to address. Poor visual outcomes we talked about. We know that there's a good portion of patients that are getting a suboptimal response. We know that those patients will oftentimes plateau at the twenty-four-month mark and continue to decline over time in terms of vision. There's a high treatment burden, which we talked about, with about a third of patients still requiring monthly dosing. And we know there's a clear call to action for new MOAs. And with UBX1325, we believe we have the opportunity to bring a novel therapeutic to improve those long-term visual outcomes, but via a proven and safe intravitreal route of administration, which we think is key. So with that, I'm going to hand it over to Mike to walk us through the science. Yep. Thank you very much, Alicia. So I'm going to spend the next couple of minutes discussing some of the data that led us to build the senescence disease hypothesis in the retina. I'm also going to go very broadly over what is cellular senescence and introduce some of the new MOA data that we've generated that help us understand how senescent cells contribute to diseases of the vasculature in the retina, like diabetic macular edema. So Unity was built on the concept that there's a unifying biology called cellular senescence that could be at the heart of several diseases of aging, and hence, targeting this biology could improve a whole series of ailments during aging. So the idea from cellular senescence came from the studies of a fellow called Leonard Hayflick in the early sixties, and what he noticed was when he was cultivating cells in a dish that they would specifically stop dividing after around fifty divisions. And so what this suggested was that there was a program that could potentially determine cellular vigor or cellular lifespan. And whenever we speak of a program, that suggests that we could potentially rewrite the code and alter the outcome of this program. So our vision of cellular senescence has evolved greatly over the past decades, and we now know that it's not just associated with aging, but several common environmental stressors, such as hyperglycemia, as we see in diabetes, sustained inflammation, and unchecked cellular proliferation, like we would have in a tumor, can all trigger pathways leading to cellular senescence. Once these cells become senescent, they still live within the tissue. They're metabolically active, but they no longer properly function. And in fact, they start producing a very broad secretome, meaning they're producing molecules that are often associated with inflammation, like cytokines, interleukins, fibrotic factors and angiogenic factors. Typically, in a healthy system, whenever a cell becomes senescent or whenever there's damage and a cell triggers pathways of senescence, our bodies are able to clear them, typically via the innate immune system. Now, with age or disease, this ability to clear senescent cells is compromised, and eventually, we start to get a build-up of senescent cells. Because they're not interacting with their environment and because they're producing these inflammatory factors, the tissue can get quite inflamed, even fibrotic, and stop functioning appropriately. At Unity, we've been trying to identify susceptibility nodes in these senescent cells to selectively design treatments to target only the senescent cells. We've done this by targeting primitive survival pathways on which only senescent cells rely. One of the examples is the Bcl-xL pathway that I'll talk about a bit later on. With this, by selectively eliminating senescent cells, we allow the environment, the cells that are not senescent in the tissue to regenerate, and this potentially could lead to long-term modification and healing of the tissue. One of the ways that we like to build confidence that a biology can translate to a treatment is to really align data from humans and animal models and in a dish. I'll give you some examples of how we built this senescence disease hypothesis for diabetic macular edema. One of the things we did is, from our clinic, we sampled vitreous right above sites of lesion, and then we profiled for some of these senescence-associated secretory phenotypes. We see that a number of these prototypical SASP factors, senescence-associated secretory phenotype factors, such as PAI-1, some plasminogen activator inhibitor, are significantly elevated, as are the interleukin six and eleven and eight. These are interleukins that are highly associated with senescent cells. Other data that you see below is from cadaver eyes, so patients that were diagnosed with diabetic macular edema upon death. The most faithful marker of cellular senescence is a protein called p16. So this is a cell cycle modulator that you see in aqua here. And what we noted was that in patients with diabetic macular edema, this p 16 was highly associated with areas of disease activity, so with the blood vessels that typically leak at the surface and within the retina. To gain more granularity as to how these senescent cells were contributing to disease process, we went into animal models. And so here's an example of a mouse model. So we made these mice diabetic by injecting them with a toxin called streptozotocin, that ablates the beta islet cells. And once these mice become diabetic, eventually they start to develop some retinal phenotypes that are akin to what you would see in a patient with diabetic retinal disease. From there, we would take their retinas, either healthy or the diabetic ones, and we use a technique called single-cell RNA-seq. The way this works is that we encapsulate every single cell in the retina and then sequence what genes are being produced by every cell in the retina. This allows us to generate these high-resolution maps based on the genetic profile and genetic expression of every single cell in the retina, and from there, we can build these models as to what exactly is happening in the disease process. What we noted was that the blood vessels from the mice that were diabetic had a very high number of senescent endothelial cells within their blood vessels. These endothelial cells are essentially the ones lining the inside of the blood vessel, and their role is really to keep the fluid within the blood vessel. A good way to understand how a cell is functioning or the way it's behaving is to look at what kind of proteins that cell is producing. Cells are primarily made out of proteins, fats, and nucleic acids. We use a technique called SILAC labeling, where essentially we label individual amino acids, and when the protein is generated, proteins are made of amino acids. We can identify what proteins are being produced by senescent cells versus healthy cells. What we noticed was that there was a very significant increase, and most proteins that were being produced by these senescent endothelial cells were cells that coded for processes of inflammation or processes related to the immune system. With this and our previous data, we can build a model where an endothelial cell becomes senescent in diabetes. It starts to produce an inflammatory secretome, and this contributes to micro inflammation within the blood vessels, but also contributes to general inflammation within the retina. One of the main functions of an endothelial cell within a blood vessel is to really make sure that the fluid and the blood stays within the blood vessel, and only selected molecules, like oxygen or nutrients or growth factors, can travel from the blood vessel and feed the tissue. And so this is done with a series of zipper-like proteins called cadherins or occludins that tie into catenins. And what we noticed was that when the endothelial cell becomes senescent, it starts to internalize these zipper-like proteins. So there's no more formation of barrier between the cells. And so when we apply a current to monolayers, so we essentially generate artificial blood vessels in a dish, and then apply a current, and see that as we add cells that are senescent into this monolayer, the barrier function is compromised. So with that, we can build the model that these endothelial cells that are senescent no longer hold fluid appropriately. So with the confidence that senescent cells are contributing to this disease process, we spent a number of years trying to identify what is the best susceptibility node or best survival factor for senescent cells that we can target, and we landed on Bcl-xL. And when we go into our diabetic retina model, what we see is that typically these mice start to produce a lot of inflammation relatively early on in the disease process. So when we treat them with our Bcl-xL inhibitors, we're able to very significantly reduce the full retinal inflammation. So essentially, we're reducing early factors like interleukin-1 beta, interleukin-6, and tumor necrosis factor, all involved in the pathogenesis of diabetic retinopathy. Because endothelial cells have a very high regenerative capacity, by eliminating those cells, the neighboring healthy endothelial cells could reform and seal the blood vessels. Now, when we looked at the amount of liquid or fluid that's being extravasated from these blood vessels, what we found was very similar to the inflammatory reduction. We were able to reduce the amount of vascular leakage from these mice. This was data that was generated by CROs, then confirmed in-house, and really gave us confidence that we're modifying the vascular environment within these diabetic mice. Now, I'll just share one last piece of preclinical experimental data. This is a model called oxygen-induced retinopathy that loosely mimics what you would see in proliferative diabetic retinopathy or retinopathy of prematurity. And so these dense white blood vessels that you see in the top, middle, panel, so these are pre-retinal blood vessels. So they grow in a zone that's typically avascular, and they eventually become fibrotic and can tear the retina from the back of the eye. And we know, with quite high confidence that these cells are, or these structures are latent with a lot of, senescent endothelial cells. So when we treat with, UBX1325, we're able to very selectively eliminate just those sick endothelial cells. And what happens, and these are the two lower panels, is that the healthy blood vessels start to regenerate and reform perfusible collaterals. And so what this means is that we're actually alleviating the ischemia or the hypoxia that's producing VEGF and a lot of other angiogenic factors. We believe that beneficial vascular remodeling might be one of the reasons why we're seeing sustained effects and why we're getting disease modification. To summarize this mechanism of action, what we think is happening is that in diabetic blood vessels, there's a subset of endothelial cells, so lining the inside of the blood vessel, that trigger pathways of cellular senescence. They're no longer able to properly form junctions with their neighboring cells, and they produce inflammatory cytokines. With UBX1325, we selectively eliminate just those senescent cells, and the neighboring endothelial cells that have a high capacity to regenerate can reform and seal the blood vessels, and hence we have a repaired blood vessel. So we recently published this mechanism of action in the peer-reviewed journal, Nature Medicine, and on the right is data that's obtained by a third-party company called Altmetric, which essentially looks at the interaction score of the articles. So they placed us in the top 1% of articles in the medical field this year in terms of the interaction with the public. And to summarize, around 10 years of Unity work, we put this video together, and I'll let you listen to it now. In advanced cases of diabetic macular edema, there is an accumulation of senescent cells in the retinal vasculature. This can cause loss of barrier integrity, vascular leak, and fluid accumulation. Dysfunctional senescent endothelial cells can also lead to the production of pro-inflammatory signals like IL-6, IL-1 beta, and TNF alpha, which can lead to disease progression. Unity Biotechnology is developing senolytic agents that target the anti-apoptotic protein Bcl-xL, which is overexpressed in senescent cells. In preclinical models, inhibition of Bcl-xL leads to elimination of senescent cells while sparing normal cells. Studies in a diabetic mouse model demonstrate that Bcl-xL inhibition reduces inflammation and improves endothelial barrier function. In animal models, UBX1325 triggers growth of healthy blood vessels and improves retinal function. In phase II clinical study in DME, UBX1325 treatment led to a sustained improvement in visual acuity and stabilized central subfield thickness. I'll now pass it over to Bob to discuss the clinical data. Thank you, Mike. It's a pleasure to review some of the clinical data with UBX1325 in patients with diabetic macular edema. And I'll show the top-line results from the BEHOLD study that have been presented over the past year, but also some new data, new analyses with this study that I think give some more insights into the activity and effects of UBX1325 in these patients. We'll be looking at the BEHOLD study, and later on, Anirvan will give some details for the ongoing phase II-B study, which is recruiting. I'm sorry, has fully enrolled, right, as we're speaking, and with results expected next year. Before going into the details of the BEHOLD results, I'd just like to underline that we are looking at patients who are not treatment naive, as we see with most clinical trial results, patients that have never been treated before and are getting their first therapies. We're really looking at people that are in the middle or advanced along their management course, okay? These are patients that have already received the standard of care, anti-VEGF, for many months or longer, and they're no longer in that rapidly rising phase of the initial exposure to therapy. They're now in the maintenance phase, in the plateau phase, of their management course, where we the goal really is just to keep them at their level, and we're not expecting any improvements, any further improvements from here. This can be seen pretty clearly in the aflibercept studies, that once they reach this plateau phase through the same period of patients that we're going to be looking at, twenty-four to forty-eight weeks, there's really little variation in the visual acuity, about one letter. So the goal is to keep them at their plateau. And I'll tell you, in my own practice, this is where most of my patients are, okay? They come into my practice. Yes, I get them treated initially, but then they stay with me forever. So most of my patients are in this plateau phase, and that's the patient population that we're going to be looking at today. So here's this design of the BEHOLD study, okay? This is a phase II study in patients with diabetic macular edema, and these are the key characteristics of the study population. They have been previously treated with anti-VEGF, as I have said, and as we found in the study, this was fairly heavy anti-VEGF treatment, okay? For inclusion into the study, the criteria were that the patients had to have received two anti-VEGF injections in the past six months, and when this data were finally analyzed, it turned out to be higher than that, four injections over the past six months. So this is an injection that these patients have been receiving every six weeks for six months or maybe longer, and I would consider that heavy anti-VEGF treatment. These are what we call the frequent flyers in our patient population. Despite this heavy anti-VEGF treatment, these patients have ongoing persistent disease. They were required by the inclusion criteria to have at least three hundred microns of macular thickness on the OCT. That's denoting that they have fluid and thickening of the central part of the retina, that macular edema, that's the definition of the disease, and in reality, these patients had over four hundred microns of central macular thickness, so fairly severe ongoing diabetic macular edema. They were also required to have poor vision. In the study, it was required that they have seventy-three letters or worse, and the more letters that you have, the better. So these patients had to have at least reduced down to seventy-three letters, and again, in actuality, these patients were more like sixty letters in the study. So fairly poor vision in this study group as well. Here's the design of the study and a couple things to point out. So prior to the screening, the patients had to have been receiving anti-VEGF, as we noted, and then at screening, the patients had a three to six-week washout, receiving no treatment, no anti-VEGF, until they get to the baseline. At baseline, they're randomized to receive either one injection of UBX1325 at ten micrograms at baseline, okay? And I'll repeat this a few times during the study. For the course of this one-year study, the patients are receiving a single injection of UBX1325 at baseline and then no further UBX over that entire year. The comparator arm received sham injection at baseline, okay? So another thing to point out about this study is there is no on-protocol anti-VEGF. There's no scheduled anti-VEGFs for these patients to receive. Rather, both arms get what's fairly standard, which is a rescue criteria for anti-VEGF, and I'll show you that those rescue criteria are fairly generous, and that's going to be, I think, an important point for this, especially in the context of how some other studies have used the rescue criteria. This then becomes another endpoint for this study. When do the patients receive anti-VEGF rescue? Do they receive anti-VEGF rescue? How many anti-VEGF do they receive? And so that's another point of comparison between the UBX arm and the 1325 arm. I'm sorry, and the control arm that we can look at. So let's look at that first. This is a Kaplan-Meier curve showing the time to the first anti-VEGF rescue, okay? On this Kaplan-Meier curve, each downward step shows one patient receiving their first anti-VEGF rescue and then being removed from the pool. Here's where I'll talk about the Unity rescue criteria. These are generous rescue criteria. In other words, we give a lot of leeway to the treating physician to give that extra anti-VEGF injection if they feel the patient needs it. Physician discretion was one criteria. If the physician thought they needed it, they could get rescued. The other is if there was worsening of the visual acuity by 10 letters, okay? A two-line loss, and this is important, or they can have that vision loss, or they can have a worsening on the OCT from their peak level in both cases, a worsening of their OCT by 75 microns or more. These generous criteria are not set up like some other studies where, you know, you had to go to war in order to give your patient a rescue criteria, talking to the study coordinators. In this case, there was a low threshold to give these patients rescue. What we see with the sham group in this curve is what you would expect to see. These are patients that have been frequent flyers. They need anti-VEGF. You take them off their anti-VEGF, and very quickly, they start to need rescue. In the case of the sham arm, shown in gray, by 18 weeks after the study, 50% of the patients had needed rescue, and through the course of the one-year study, 80% of these patients will require their first anti-VEGF rescue over the study, fairly steady. In contrast, the UBX1325 arm, after a single injection of this drug, has an initial delay in needing their first anti-VEGF rescue, and then about by twenty weeks, for the patients that didn't need anti-VEGF rescue, for the remainder of the study, you can see that there are very few patients then that would go on to need that rescue. The curve flattens out there so that it never even hits the median for time to rescue. By the end of the study, 53% of the patients over the course of a year had required no anti-VEGF rescue after a single UBX1325 injection, and this was significant compared to sham, of course. So this is a sign that UBX1325 is altering the natural course of this disease in ways that we wouldn't expect. Let's look at some efficacy endpoints now from the BEHOLD study, and I'll just show these top line outcomes, and this is looking at change in visual acuity from baseline. It's a standard measure of how these patients do from baseline to 24 and 48 weeks. And you can see with the blue bars, with UBX1325, we are seeing a vision gain in these patients. And again, I'll repeat, these are patients that are supposed to be at their plateau. The goal in normal practice would not be to get further visual improvement. It's to keep them and maintain them without further visual loss. But instead, here in this, after a single injection at 24 and 48 weeks, we're seeing a six-letter gain, okay? And that equates to more than one line of visual acuity, so that's something that gets our attention here for patients and maybe something that we wouldn't expect to see. As opposed to this is the sham group, where we do not see any significant visual improvements, as you would expect. Looking at the second major criteria, which is the change in the macular fluid and the macular thickness that we see on OCT retinal imaging, first, let's look at the gray bars with the sham. No surprises there. When you have patients that are requiring anti-VEGF, and you take them off of their anti-VEGF, over 24 and 48 weeks, there's worsening of the macular fluid and the macular thickening on OCT, and you can see that there's about a 35 micron increase on average for these patients over that time period. UBX1325, by contrast, maintains the anatomy of the retina. There is stability of the OCT after a single UBX1325 injection. So at 24 weeks, this was a reduction of about six microns, staying stable, and by 48 weeks, this was about 13 microns. So stability of the OCT over this one-year period. This is looking at the number of injections and the patients that required injections. Again, I'll repeat that in the UBX1325 arm, 53%, a majority of the patients did not require any further anti-VEGF rescue over 24 and 48 weeks, and this is compared to the sham injection, where only 21% of patients were able to remain rescue-free over this time period, and many of them, about half of them, required two or more injections over the course of that study. Safety is an important consideration in any phase II study, and especially with some things that we've seen in the retina community with new drugs, we are on the lookout for ocular inflammation and serious side effects that can occur in the eye. There was an overall favorable safety profile with UBX1325, and importantly, we did not see any instances of serious intraocular inflammation, no instances of vascular occlusion or vasculitis, the things that we are looking out for, so a favorable safety profile with this drug. I'll close by talking about an analysis that is, as Anirvan was saying, a new analysis from the BEHOLD study, and this is actually the first time that this has been presented to the outside. This is a pre-specified endpoint for the BEHOLD study to look at diabetic retinopathy severity score, DRSS, which has become another standard parameter to look at diabetic eye disease. I'll make the point that this DRSS is a independent - not independent, but it's distinct from looking at diabetic macular edema. So this is another aspect of diabetic retinal eye disease. Just to show you what it looks like, from the normal eye shown here on the right, you can see a diabetic eye with these retinal hemorrhages. Now we're looking at the entire retina, not just the central retinal macular portion, but we're looking at the entire retina, and we count up the number of the retinal hemorrhages, the severity of the retinal hemorrhages, and that way, a score can be assigned by the Duke Reading Center, in this case, by a masked observer, to say, what the score is between 0 and 6 on the DRSS score. I'll note that it's been recognized by the FDA that this is an approvable endpoint for label indication, for example, if there is a two-step change in the score. So a two-step change, for instance, would take, as shown in the bottom graph here, would take an eye with severe non-proliferative diabetic retinopathy and shift it down to moderate non-proliferative diabetic retinopathy, or in another case, a patient that had baseline, moderate, DRSS score would be shifted down to mild. So considered significant changes in the overall retinopathy. I should point out also that at baseline, this was, the DRSS scores were very well balanced between the UBX arm and the control arm. And this is what was found at 24 and 48 weeks. The percent of patients that met this criteria of a two-step reduction in the severity of their retinopathy was 30% in the UBX arm at 48 weeks, and you can see a trend for that increasing over the course of the study. In the control arm, you can't even see the bars here because it's a zero on this graph. No patients in the control arm had a reduction in their DRSS. So again, showing that there's an effect on the retinopathy distinct from this effect that's seen on the diabetic macular edema. This is another way of looking at this score, looking at the distribution of step changes on this DRSS score. Again, in the control group, shown in gray, you can see that no patients achieved visual acuity stability, and the bar there on the left is showing in the gray the patients that lost or that worsened on their DRSS. This is in contrast to the UBX arm, where the distribution is shifted to the right, towards the improvement in the DRSS score. And as we said, 40% of the patients had some improvement in their DRSS score over a year after a single injection of UBX1325. And as we showed, 30% of those patients met that FDA's threshold of a two-step improvement in their diabetic retinopathy severity. So again, another sign that UBX1325 is having activity and an effect on these eyes, not just on the side of diabetic macular edema, but also on a different parameter of the severity of the overall retinopathy. So I'll summarize. The BEHOLD study showed that at 48 weeks, these patients showed a gain of 6 letters in visual acuity after a single UBX1325 injection. 50% or more of these patients went through the entire course of the study without needing any further anti-VEGF rescue. The macular structure, the anatomy, was well-maintained over the course of the study, keeping stability at this plateau phase of the disease treatment, and there was a good overall safety profile of UBX1325, with no instances of intraocular inflammation. So with that, I'll turn it back over to Anirvan to discuss the ongoing phase II-B study. Thanks, Bob. So, in this section, I'm going to review with you the design of the ASPIRE study. I'll talk a little bit about our FDA interaction and, also comment on our CMC readiness for a pivotal study. So here we show the design of the ASPIRE study, and so I'm just going to walk you through it. There are a few elements that are somewhat different from BEHOLD, but fundamentally, it's actually a very similar study. So first of all, with regard to the patient population that's shown at the bottom left, you'll see that the patients who are recruited into this study are very similar to the BEHOLD population. These are patients who have been on an anti-VEGF for at least six months, and despite that treatment, still have residual visual acuity deficit and fluid in the retina. So the criteria are quite similar to what you had seen before, even tightened a little bit further in that their maximum vision coming into the study can be 70 letters, or between 70 and 30 ETDRS letters. It's a one-to-one randomization between a UBX arm and an aflibercept arm. Now, if you look at the design, you'll see on the left-hand side, you see three injections, which are run-in injections of aflibercept before the patients are randomized. And the reason for that is that we want to make sure that the patients have absolutely reached their plateau before they get randomized on one of the arms so that we do not see an inadvertent effect of aflibercept when they should have plateaued. Like, the whole idea is to look at plateau patients and what improvement can we provide?... So those three injections ensure that by the time they get to randomization, they should have gotten to their anti-VEGF plateau. And per requirement for entry criteria, even at that point, they have to have significant fluid in the eye, and they have to have poor vision, right? So these patients will qualify as people getting a lot of treatment, but inadequately responding to treatment. When they get randomized on the aflibercept arm, the treatment is per label. So they get an aflibercept every eight weeks. So you see injections at zero, eight, and 16 weeks, with a primary outcome data readout at week 24. So the primary endpoint of the study is 24 weeks. And as you've seen in prior studies, by that time, you have a good sense of what the maximum vision benefit should be. On the UBX arm, you'll note that the first injection that they get, it has a dual injection of aflibercept and UBX, and the reason for that is that what we noted, and Bob highlighted, is that when you take patients off of an anti-VEGF, pretty quickly they'll start accumulating fluid. This is expected, right, and during that rebound period, you can end up having these rescues in patients, and then, of course, post-rescue data is not counted in the study, and we also saw that the UBX effect takes around eight to 12 weeks to kick in because there's a lot of retinal remodeling that needs to happen. You saw that the senescent cells need to be eliminated. You need to reduce inflammation, you need to reduce vascular leak, improve perfusion, and then vision will improve. So the first injection really allows us to clamp the CST in a stable place until the UBX effect has kicked in. You'll also see that in this study, you have UBX injections also at week eight and week 16, and there are a couple of reasons for that. One is, while we saw very impressive gains after a single injection of UBX, we don't know whether that is the maximum benefit that patients might receive. Now, based on the mechanism of action, we believe that you should not need to have to continue to treat a patient with the UBX, as you do with aflibercept. But this way, if there are any remaining senescent cells in the vasculature, the second or third injection might allow you to clear them all out so that then you can be in a phase where you don't need additional treatment for some time. The second reason for that is that this is a true match treatment. You see, there's an aflibercept, there's UBX. So every once in a while, you end up in a design where the two treatment arms are, you know, initially treated somewhat differently, and there are questions about how much did that impact it. So whatever result we get from here, there'll be no question as to advantaging, you know, UBX in any way compared to aflibercept, and we'll see the maximum benefit of UBX. Week 24 is a primary endpoint, and then we extended the study to 36 weeks, so there'll be a second readout at week 36. Finally, at the bottom right, we talked about the endpoints. The endpoint for the study, the primary endpoint is gonna be BCVA change from baseline, which is also the approval endpoint. We will also measure CST change, as Bob mentioned in the BEHOLD study, and a number of other measures that are standard for retinal diseases, including the diabetic retinopathy severity score, which Bob just reviewed with you. Now, when we design these studies, we're looking to have a study that can largely move forward to a pivotal study with minimal changes, because you don't want to take risk when you go from a phase II to a phase III study. That's a big study. That's the registrational study that will lead to, ideally, to the approval of a drug. Now, we wanted to make sure that our thinking of ASPIRE was in, on track, in line with that expectation, and we recently had an interaction and Type C meeting with FDA, which largely confirmed that. We're gonna share additional details of that interaction as time goes on, but at this point, I just wanted to kind of point to kind of some high-level learnings from it. Most importantly, the design of the pivotal study would broadly be in line with the phase II study. It is. There's an alignment that the endpoint for that study would need to be BCVA change from baseline, which is the endpoint that we saw in BEHOLD and which is the endpoint that is in the ASPIRE study. We also have clarity on the margin of non-inferiority, so the non-inferiority margin will need to be four letters, which has been also typical for other non-inferiority studies for drugs that have been approved in the last few years, and finally, we have clarity on the comparator, which will be aflibercept, an anti-VEGF, that would be expected to be dosed every eight weeks, which is what we are also doing in the ASPIRE study, so based on this feedback, we feel very encouraged that the way we've been thinking about ASPIRE was the right way to think about it, and we also believe that the ASPIRE study will be quite informative in terms of the likelihood of a pivotal study succeeding. I just want to also comment on CMC. It is, it's a part of every drug story that often doesn't get visibility. You only hear about it when something goes wrong. But I do want to take the opportunity to highlight the fact that we have a drug product that is frankly, when you look at other, you know, comparable drug products, one that has a defined and reliable way of manufacturing. We most recently completed a pivotal study in manufacturing runs, so we're in very good shape to be able to initiate a pivotal study. I'll also use this to remind you that UBX1325 is a small molecule inhibitor of BCL-XL, right? Small molecules, as you know, the world of therapeutics out there is largely small molecules and large molecules. Anti-VEGF is a biologic. Biologics, typically speaking, have a significantly higher cost of goods, can be a more complicated path to synthesizing that product. With UBX, we have a fairly straightforward path to creating drug substance and drug product, and so far we've been lucky, and we've had really good stability of this drug, and the manufacturing continues to be quite smooth. So we feel good about our readiness to move this product into a pivotal study. With that, I'm going to invite Alicia to come back up here, and also we'll have two of our retina specialists join for the last part of this talk to talk about DME and the opportunity for UBX. Alicia? ... So at this point, as Anirvan mentioned, we wanted to invite a couple of folks to join the call, both Arshad Khanani and Dante Pieramici. Hello, both. Hi, Alicia. Good morning. Good morning. Good morning. So what we'll do is do a brief introduction and then head into a couple of questions. So starting with Dr. Dante Pieramici, he is a partner at the California Retina Consultants and Advisory Board member of the Retina Consultants of America. He has held full-time academic positions at the Johns Hopkins Wilmer Eye Institute and the Yale Eye Center, has been a principal investigator in more than 100 clinical trials, published hundreds of peer-reviewed papers, and book chapters as well. Dr. Pieramici has served as an advisor, consultant, and steering member for many large clinical trials, exploring novel treatments in retinal diseases. Welcome, Dr. Pieramici. Dr. Khanani is joining us as well this morning, who founded the Clinical Research Department of Sierra Eye Associates, which is now one of the leading clinical research centers in the country. He has served as a principal investigator for over 120 clinical trials. Dr. Khanani serves as the chair and member of numerous national and international clinical trial steering committees, and is a distinguished member of the Macular Society and the Retina Society with 150 scientific publications. Welcome, Dr. Khanani. You know, we've heard a lot today about DME patients, the disease progression, and you're treating these patients every day in your practice. We'd love if we could just hear from you. You know, what do you consider when you're selecting patients for treatment? Thank you. I can get started. Good morning, everybody. It's a pleasure to be here. So, you know, DME is a disease of young, working patient population, and when they come in to see us, most of them have pretty advanced disease, and, you know, obviously, the primary modality of treatment is frequent anti-VEGF injections. So for me, you know, I try to use the latest agents so that we can minimize the treatment burden. But even with the new agents, even with dual inhibition, with faricimab, we're stuck with, frequent injections for these patients, and there's a big, treatment burden. And on top of that, as you mentioned, you know, many of these patients, 30 to 40 to up to 50%, are suboptimal responders, and we have not seen visual acuity outcomes better than what we saw with early days of Lucentis. So high treatment burden, you know, frequent clinic visit and injections that leads to, you know, suboptimal vision outcomes because of lack of compliance. So as a field, we're still looking at agents that are more durable, can and also can improve outcomes that are better than current standard of care. Mm-hmm. Anything you'd add, Dr. Pieramici, from your point of view? Yeah, I think Arshad summed it up very well. I mean, before the era of anti-VEGF agents, we didn't have a lot for our DME patients. We used to do laser, and the main goal in the laser is just to stabilize things. Anti-VEGFs changed everything. I think that we, the first thing we pull off the shelf, of course, is an anti-VEGF agent. But we, in a lot of these patients, we're pulling this anti-VEGF agents very frequently, every month or two. And as Arshad mentioned, a lot of the patients, despite frequent injections, don't get the visual results or the anatomical results that we want six months or even farther down the road. So it's nice to have other things. We've used steroids in the past, but they have side effects, glaucoma and cataracts. And so it's exciting to think of having another, a drug with a different mechanism of action. And when I see a diabetic patient, I'm thinking about a lot of things. We really customize care for these patients because they're, you know, they're not all like the clinical trial patients. Many of these patients are quite sick, and they have to see frequent doctors. I mean, shoot, I have trouble getting to my doctor once or twice a year, let alone have to go to a doctor's many times a week. So not only to have an agent that works better, is more efficacious, but one that may increase the durability and reduce the treatment burden will be massively impactful for these patients. Mm-hmm. And one of the data points we were looking at earlier, as you saw in the conversation, was the fact that, you know, a third of the patients may not have that ability to drive at a later date. Can you elaborate on that, just kind of the age of this population, anything further to add in terms of that unmet need? I guess I'll continue with that, and Arshad can finish. Yeah, these are younger patients. They're not like the neovascular AMD patients who are generally a bit older and probably retired in many cases, and some of them, frankly, just enjoy coming to the office to talk to us and things. But these younger diabetic patients, many of them are working still, and or, as I mentioned, have a lot of medical problems, so they're spending time at my office, they're in an endocrinologist's office, their renal doctor's office. So yeah, for them, it's a really difficult thing to come in for frequent evaluation and treatment, and they really want to continue with their life. They're young people. Not that old people don't want to continue with their life either... but I think that, these folks are real busy, and it makes it difficult. Arshad? No, I agree. I think, the key is that, you know, getting an injection in the eye frequently, what happens is they have to miss a day of work, they have to find a driver. Many times, this is a bilateral disease, Alicia, as you mentioned. So coming in for bilateral injection, they definitely cannot drive, and then, you know, it brings a big burden on them as well as their family members and also on society. Many of these patients are scared to miss their work because they have to come once a month initially, and they actually, you know, don't come in because of that reason. They have to also account for the cost of care. As Dante said, they have appointments with their nephrologist and podiatrist and endocrinologist. It adds up. But one thing I want to highlight is that how can we optimize outcomes for these patients, right? So many of these patients are not getting to 20/40 vision, even with the current treatments, and that's actually a good number of patients, and you need that to drive. So having, you know, new agents that can get a line of vision, I think it's gonna be a huge impact on society and on the quality of life for these patients. And then, of course, having something durable that can last three, six, nine, or 12 months. As a field, we are looking at that, that is delivered in clinic, is important, not a surgical option, because then obviously, you know, the uptake is much less because of the cost of OR and the risk and benefits. I think those are the things I'm thinking: How can we work together to have better options and better outcomes for our patients, which will eventually lead to a positive impact on them, their family members, as well as the society? Mm-hmm. Thank you for just painting that picture of the patient and kind of the day-to-day that you're experiencing and trying to help patients with in the practice. Dr. Khanani, you mentioned the six letters, and maybe we can play that through a bit further. We heard from Dr. Bhisitkul, you know, earlier in the presentation, talking about the BEHOLD study. You were both investigators in that study. You know, maybe you can comment on what were some of your key takeaways. What stood out to you in terms of the findings with that study? I think I want to highlight four things that are important as an investigator and also looking at the data. As you know, Dante and I are very data-oriented. We stay true to the data. The first thing is that you are getting improvement in visual acuity in these chronically treated patients, as Bob did a great job presenting that data, which is not possible with the current standard of care, and we have not seen many programs achieving that. Number one. Number two is, you know, based on mechanism of action, as Mike presented the work so nicely, is stabilization or improved anatomy. So I think it's a different MOA, and, you know, I think people need to consider that we are getting rid of these senescent cells, and we are stabilizing disease, and it doesn't give you the rapid, you know, drying effect. But stabilizing or improving anatomy over time is a clinical outcome that we are looking at. Number three is the durability of treatment, over 50% of patients not requiring a supplemental injection. And as an investigator, I was actually allowed to supplement these patients as needed because I like trial design, where I have a lot more flexibility because obviously you want to make sure that patients are a priority. And number four, and one of the most important thing, is safety. So for a new MOA, we need to make sure it's safe. We did not see any cases of inflammation or other events we are concerned about, so those are the four learnings for me, and that's why I was excited to participate in the ASPIRE study after looking at the BEHOLD data. Dante? Yeah, I agree. I mean, I've been intrigued by this mechanism of action, this, you know, senescent cells and eliminating senescent cells, and and how this might help. I mean, initially, I sort of thought in my mind this would be a great treatment for geographic atrophy, AMD-type patients. But after listening and seeing the preclinical work that's been done with the, uh, diabetic model, I think it's extremely intriguing as a separate mechanism of action for these patients. And, you know, and the preclinical work is very compelling, and then we bring it into the clinic with the BEHOLD trial, and we see a lot of things happening that make us convinced that there's something new or something different going on with this mechanism of action. We're not only seeing we're squeezing out some additional visual improvement in patients that have had frequent anti-VEGF injections. So we've maximized, in a sense, the anti-VEGF effect, but we're still able to squeeze some more visual out. So there's something else going on. Second of all, I think the new data that Bob presented today, Bhisitkul, with the DR data, again, that's intriguing too, that we're able to squeeze out some additional changes in the diabetic retinopathy status. So there's things going on with this mechanism of action that I'm intrigued by. And based on the fact that it seems to be a very safe agent, I mean, this is a small molecule. It's not like the biologics, where we're becoming increasingly concerned about inflammation in the eyes. We're seeing even in some of the newer agents we didn't see in the clinical trials, but we're starting to see vasculitis events and things like this. These are difficult molecules. I mean, the gene therapies are gonna be even more difficult, I think, as they come to market with safety issues. But a small molecule add-on that we really saw essentially no safety problems, I think is compelled me to want to investigate this further. It. You know, these are patients, again, that we've maximized, in a sense, or the anti-VEGF approach, and now we're looking for something else, and this seems like this could be that something else for some patients at least. Mm-hmm. Mm-hmm. Thank you. You know, I think to fast-forwarding to the present day, with the ASPIRE study, we know that we've completed enrollment, as covered earlier in the presentation. You both being investigators in that study as well, maybe you can comment to change it up around recruitment and enrollment. What was that like for you? Anything you would share? Yeah, I think I can get started. We were excited to participate based on the data to date. You know, in BEHOLD, as we discussed, we saw multiple signals of positive activity, as Dante and I mentioned, going in the right direction. You know, for me, we have so many trials that come through us, and I don't participate in many of them because I'm not sure about the safety, I'm not sure about the efficacy, and I'm not sure about the unmet need. For example, I don't do biosimilar trials because we have approved agents. Here you have a new MOA that's shown to be safe and efficacious, and you talk to your patients about that. You know, you treat them like your family members. You say, "You're coming in frequently. We have not optimized outcomes in terms of vision. We may be able to squeeze out some more vision," as Dante said. And you know, it's a safe product, and it is being studied earlier, and it has solid preclinical science behind it. And guess what? Pretty much everybody wants to sign up for it. Why would you not sign up where you're getting either standard of care or a new molecule that can actually get more vision? So it was very easy to, you know, discuss with patients. And obviously, you know, being excited about the data myself also translates into them being excited. So yeah, it was very smooth for us. Patients were very motivated, and just the efficacy and safety profile really helped with that enrollment. Mm-hmm. Mm-hmm. Anything to add to that, Dante? Yeah, I agree, Arshad. I mean, you know, imagine you're a clinician sitting in the clinic, right, and the patient comes in, and they're a brand-new patient with diabetic macular edema, well, we have standard therapy, and, you know, recruiting a naive patient can be difficult because they'll say, "Well..." You know, again, remember, they want to get in and out of there. They'll say, "Well, you can treat me today, or I can join a trial where I got to come back and..." so recruiting the naive patients can be difficult because we have a standard therapy. The patients that we're putting in these trials, again, are the patients that are not naive, that have had treatment experience, and so that it's a whole different conversation. Now, we've been doing these injections for a number of months, we're getting some improvement, but we'd like to do better. We do have a possibility of being part of a clinical trial. You know, people are much more enthusiastic at that point because, you know, we've sort of weeded out the patients who are going to respond extremely well to anti-VEGF agents, and those are the ones that really we don't need another drug for. But the fair number of patients that don't have adequate response, they're now sitting in the chair and thinking: "Yeah, I'd like to try something else." And so I think recruiting for the ASPIRE trial was, you know, is easier. I think going forward, if we continue with this population of patients, it'll be... There's lots of them in our practices right now, these patients who haven't had adequate response, or maybe we can benefit them more with another agent. So yeah, I think that as I think about how we're going to recruit these patients, these are much easier to recruit than the naive patients. Don't you agree, Arshad, or? Yeah, no, I, I totally agree. Yeah. Mm-hmm. Mm-hmm. So let's round out with just one more question here. You know, in the bios, clearly, you've been a part of so many different clinical trials, programs, et cetera. You know, what is different about this UBX1325 program in your mind? Maybe Dante, you could kick us off. Sure. Well, I mean, we've already talked a lot about it. It's a different mechanism of action. We're trying something completely new. It's not, you know, another anti-VEGF or an anti-VEGF with another molecule attached to it or a longer-acting anti-VEGF. I, you know, I think we're really looking for not just durability, which a lot of people are going for. We're looking for efficacy and durability in this agent. I think we're looking to get more out of it for our patients. And, you know, if you look at, if you poll retina specialists, what's needed, the two things are something that's more efficacious and then something that's more durable. And I think that this agent, at least from what we've seen so far, may check off both of those boxes. It seems to be extremely safe, which is nice as well, 'cause you never want... The first thing is to do no harm, particularly in clinical trial patients. So, you know, we're adding something on that has a real possibility of making things better and increasing the durability. In my mind, that's why I'm enthusiastic about this. Mm-hmm. Dr. Khanani? Yeah, and I can follow up. I mean, I think, as Dante said, almost all trials that we participate in are looking at durability. Very few are looking at visual acuity gains. We have some late-stage programs in neovascular AMD, but in DME, really there's a huge unmet need. I think I'm excited because I know biology is complicated. As a field, we have simplified it too much, of course, VEGF being the primary target, but there's a lot more going on here. And kudos to Mike and his team for doing this work for the last decade to really help us understand biology of these senescent cells. And so for me, my goal as a physician is to achieve the best outcomes- ...for my patients in a safe fashion. You know, we are in the business of vision, and patients come to us because they have a problem, and that's they want to optimize their visual outcome. So here, you know, when I see UBX1325, number one, opportunity to improve vision. Number two, better durability, so less treatment burden, meaning possibly better outcomes in real world. And then number three is obviously, it's done in clinic with an intravitreal injection that everybody is used to doing. So that's why, you know, innovation is not easy, comes with challenges, comes with difficulty. We have been on this, you know, goal to optimize outcomes for our patients. And I mean, this is as close as it has gotten in DME for us. So that's why I'm super excited to see what the ASPIRE data shows, and hopefully it will show a positive, data set, so we can move into the pivotals and have this product available for patients around the world, so they can improve their quality of life. Mm-hmm. Yeah. Well, thank you. Thank you for what you're doing for patients first and foremost, and also for sharing your thoughts with us today. So, Dr. Khanani and Dr. Pieramici will be with us for the Q&A section. But with that, I will hand it back over to Anirvan. All right, thanks, Alicia. Well, actually, I want to invite Alicia, why don't you stay on, and we'll just move to a short Q&A. So Bob- Yep. And Mike, why don't you come up here? Arshad and Dante will stay with us. We have a little bit of time here. We'll take some questions, if there are any questions in the room, and of course, we'll be here right after the event to talk to you and kind of elaborate on any of the elements. But yeah, so again, Doctor Khanani, Doctor Pieramici, thanks so much for joining. It is super early, and like, living in California - I feel their pain, because you had to wake up at four in the morning or before that to take it, so shows real dedication. And this partnership is so important, right? Because as I mentioned, you know, if a patient comes in, there is an approved treatment, the easy path is to just say, "Okay, like, just take some anti-VEGF." So it takes a lot to understand why a patient might benefit from a new treatment option, getting them into study. There's a variety of reasons why patients don't qualify. As you saw our treatment, you know, the inclusion criteria are really tight. They have to be in a certain band of vision, certain amount of fluid. And I have visited both of their sites. They're incredible operations, and they're doing great service, frankly, to the field. So aside from UBX1325, they've been really fantastic. And, and have helped us really think about, you know, the patients who are most in need, where UBX1325 could be valuable and, and excited to, to continue to see, you know, directionally positive signals from UBX1325. The DRSS analysis that you shared, Bob, was something that was defined in our, our primary analysis set. We, of course, at that time, focused mainly on BCVA and CST, which is where people go to first, which is particularly for the DME path. But DRSS is, is a good measure of what is happening overall in the retina, and, and seeing that consistency, I think, gives us a lot of confidence in, in this program. So I'll open it up for any questions in the room, and then we'll go from there. Salim? Yeah. Oh, thanks. Salim Syed, Mizuho. So three for... Thanks for all the color today, guys. So three for me. Just on the, so you talked about the actual baseline characteristics in BEHOLD, and I presume you guys have looked at the baseline characteristics for ASPIRE, right? Even though it's not disclosed. But could you confirm for us that quantitatively you're getting into that same sort of region, so around four injections in the prior six months, you know, the same with the retinal fluid and the visual acuity? So and two other questions, maybe just- Okay, so I'll start with that. We have not shared any information, as you know, about baseline characteristics, et cetera, in prior patient population. But in broad terms, I can tell you that the patient population is similar in terms of, you know, having six months of treatment prior. We expect the injections to land in a similar zone, and so I would not expect surprises in the patient population. So there's nothing in the baseline characteristics in your mind that? Nothing that stands out saying like: "Oh, this is a whole different patient population. Right. Okay. And then just on BCVA, I don't think you mentioned it, but what are you powered to see in non-inferiority for ASPIRE? We also have not shared that publicly, so, but we'll share that as we get closer to data. Is there a reason why you can't? I mean, so you're doing four letters in the phase III slide, right? It's four and a half letters. That I can say, right? So it's, it's powered to detect four and a half letters with high confidence. Four and a half in ASPIRE? Yes. Okay. To your point, this is an important point, right? So it's powered to see four and a half letters, but of course, in the analysis, we'll be able to see in the real data set what that margin looks like, right? Would it have met a four letters? Obviously, the pivotal study would be larger, and hence getting to four letters in a larger study is easier. But it's four and a half letters. This study has 50 patients in it. Okay. And then just lastly, just given the multiple doses, is there any theoretical safety talks, concerns with moving from the single in the BEHOLD to multiple? I know we kind of talked about the safety of this. Yeah, no, there isn't. I mean, and it's an important point because it largely has to do with the fact of the residence of the drug and its clearance from the eye, right? So that's another important difference compared to anti-VEGF. So you inject it, and you're like a PK-driven effect, so the drug stays in the eye for some time. In our case, it's the biology is really driven by the pharmacodynamic effect. So the drug itself gets cleared from the eye in just a few days, well before you get to a second UBX injection. So it has been our expectation, and this is also that each injection is effectively an independent injection. So there's no additional safety implications for the second- Is it also getting cleared from the body as well, if it- Yes, in the body, it's undetectable. It's undetectable. Right, so intravitreal injection, the levels are below detection in the serum, so there's none of—there's no detectable UBX- Even with multiple- Even with multiple... Yeah, there's no detectable drug in the system, and in the eye, it gets cleared within a few days. Okay. All right. Thank you very much. ... Brandon? Brandon Folkes, Rodman and Renshaw. Maybe just for the guests on the panel, when you think about UBX1325 as a new mechanism of action, and jumping ahead, assuming it's, it is approved, how do you think about how well, well-defined a dosing schedule initially, as well as patient parameters will need to be, especially in the sort of broader prescribing community outside of the academic institutions, right? So we've talked about sort of the broad application of 1325, you know, following on Salim's question, just sort of on patient baseline characteristics. If we think about once it's approved in the, you know, community setting, how well-defined do you think those parameters will need to be initially, given it's a new mechanism? Yeah, well, let me start, and then maybe I'll hand it to Doctors Khanani and Pieramici to comment on what it might look like in a real-life setting. So, the elements of the ASPIRE design, to some extent, I think, kind of anticipate what a transition treatment might look like, right? So, you have patients in the clinic who are not responding optimally to an anti-VEGF. And so to move to this new mechanism of action, then, you know, we'd expect then them to either have one or maybe more than one injection of UBX, and then they can be in a kind of long-term treatment with UBX. The number of UBX injections is really the final injections is still to be determined, and will be informed both by the BEHOLD data and the ASPIRE data, right? In our minds, our expectation, the window is somewhere in that one to three injection range. And beyond that, we expect significant durability, as we saw in BEHOLD, right? If that were to be the case in ASPIRE as well, then we would expect that after those transition doses of, let's say, somewhere between one and three, then they're maybe getting one injection every six months or so. And the reason for some level of continuing treatment is too: most physicians we talk to want to see their patients, make sure everything is going well. And senescence, you know, in this case, the senescent cells are accumulating in the background of diabetic disease, right? So although we're treating the eye and it can, you know, eliminate the senescent cells, these patients have had diabetes for 15, 20 years, so they're in a chronic state. So it's entirely possible that over time, you could accumulate more senescent cells. So at some periodic level, a treatment that, you know, clears the senescent cells could be valuable. But maybe, Dr. Pieramici, you can start out by talking a little bit about, like, if you have a patient in real practice in the future and thinking of them going from an anti-VEGF treatment to UBX, what might that look like? Yeah, I mean, I think it's gonna look a lot like in clinical practice what the ASPIRE study's design is. I mean, the patient's gonna come in. They're gonna have, say, a newly diagnosed patient with DME. We're gonna start with anti-VEGF injections, right? And if the patient responds, and they dry up, and their vision's fine, we generally start extending the therapy. That's how it's done in the real world. And, you know, clinical trials are guidelines. Clinical trials are for getting approval of the drug, but how retina specialists use it is generally kind of in this prescription. And then for the patients that are not gonna be infrequent, but the patients that still have thickening after multiple anti-VEGF injections and haven't gotten to, say, 20/40 vision, or we still think there's vision on the table, this will be an add-on just like it is in the trial. We're gonna, you know, we'll do a lead-in with anti-VEGF injections, and then we'll add this to our armamentarium for these patients. And then we'll try to extend follow-up, and there'll be all sort of things. So that's just how we roll as retina specialists. I mean, there'll be a lot to learn about this drug after it comes out. The main thing is to get it approved and start being—you know, show that it has a benefit and a safety and, and then get it—put it in the wild, and then, and lots of things will be done and learned, as we go forward. Arshad, do you— Do you guys agree? Yeah, I mean, I totally agree. So, you know, Dante is in a retina-only group, I'm in a multi-specialty group, and Bob is in academic setting. So all of us have different practices per se, but I think we all agree on the fact that we will know that a DME patient is responding well or not in the first three injections or so. So most of the patients gonna show us if they're gonna be great responders, moderate responders, or suboptimal responders. So when a new drug comes out in the market, it's always used in patients who are higher need or have uncontrolled disease. We have seen that with faricimab, with Eylea, with brolucizumab. I expect that, you know, patients who have chronic fluid, even though they've been in my clinic for a long time, or new patients after receiving three or so anti-VEGF injections that persistent disease. Essentially any patient that has the potential to get more vision. I think drugs get broadly adapted once they're approved based on physician's discretion, which is great thing about retina, is that we all try to do what's best for our patients, and each patient is different, and that's why we want to optimize the outcome. But certainly, the start would be higher need patients, patients with lower vision, and then as we establish safety six or twelve months after the real-world uptake, then I think it even goes broader. Bob, what do you think, based on your practice? Yeah, I think the clinical trial is never going to tell us entirely how to use this drug and which patients on which to use it. To me, what's gonna be very interesting is, you know, clinical trials look at one year or two years of the disease, and for most of our patients, the diseases are twenty-year diseases. So I think a really interesting question, which we will probably have to figure out, is what do you do after a year? Do these patients, they're still going to be accumulating senescent cells. You can eliminate all those cells for a period of time, but at what point will there be enough reaccumulation that you'll have to start a second round of this treatment? And I think that's gonna be, for the first time, us people are going to have to make some determinations and use our judgment there. Because in the past, anti-VEGF, it's very simple: give the drug and keep giving it until either the patient dies or you die, basically. And here, we're gonna have to develop some nuance. Thanks, Bob. Yigal? Hi. Thanks, Yigal Nochomovitz from Citi. I had a question for Dr. Bhisitkul on the DRSS analysis. Did you look at that as well by breaking it out between the 47% that had the rescue and the 53% that didn't? I'd be curious what the DRSS was in the non-rescues. So maybe I can— Go ahead. I can comment on that. Yeah. So the way that analysis is done and that, and frankly, the way we looked at, is you can see that all the post-rescue data is edited, right? The way we did the MMRM analysis for BCVA CST. So it has all the DRSS scores for all the patients. If a patient ends up getting rescued, then their subsequent data is edited so that it's not contaminated with anti-VEGF. So that's the analysis you have specified, and that's the one we have done. So we don't have a separate analysis with just the patients who did not get rescued or just the ones who got rescued. Ah, okay. Understood. And then with regard to the ASPIRE trial, can you talk about any powering assumptions on the% rescue that you would expect in the period from the 16-week point to the 24- to 36-week point for both the UBX1325 and what you would expect to see for aflibercept in the control? How is that structured? Yes, it's an important question and obviously an important part of the data set. So first of all, the main reason to extend it from 24 to 36 was to generate kind of the first look at some level of durability data and what kind of rescue that you need. So there'll be about a 20-week period between the 16-week injection and the 36-week injection. Now, on the UBX arm, I would say that the relevant background information we have to go on is from the BEHOLD data. So in the BEHOLD data, we saw there was about a 50% rescue getting to six months, and then that kind of essentially, there were no additional rescues later on, right? So, if it would be something similar like that, that might be a, you know, assumption of what you might expect, what we'll see in this data set, what that looks like. On the aflibercept arm, and I'll say the only reason it's a little hard to predict is that the patients who come in are kind of the worst of the patients, right? So if you look at reference studies from faricimab, Eylea, et cetera, you'll see certain rescue rates expected, but that's a naive patient population, kind of all-comers patient population, and in that population, you can see what the expectation would be of rescues over a twenty-week period. And in this case, these are patients who were pretty high need coming in. So you saw that in BEHOLD study, at least, they were needing an injection every six weeks, right? So if you take that patient population, it could be that aflibercept arm might need a bit more rescue than a historic aflibercept study, right? That, I have no data to support that, but just knowing the kind of patients we're enrolling and the kind of burden of injection they have had previously. Does that make sense? Okay. Yep. Thank you. All right, Matthew. Hi. Thanks, guys. Matthew Caufield, H.C. Wainwright. As a follow-up for the KOLs, is there any distinction between ultimately using thirteen twenty-five with aflibercept versus faricimab patients, for example, if approved? Or the patient identification would really be driven by the overall response to standard of care? Okay, Matthew. Actually, may I direct this first to Dr. Khanani, because I know you treat a lot of faricimab patients, a lot of aflibercept patients, so maybe you can speak to that. Yeah, absolutely. Matthew, great, great question as always. I think the key is the focus on vision. So with dual inhibition, of VEGF-A and Ang2, with faricimab, we have not seen better vision outcomes. We have seen some anatomic improvement compared to aflibercept in the trials. It's mainly the faster drying. We are getting to outcomes that may be slightly better in terms of anatomy, though we have not seen the visual acuity benefit. So again, we're in the business of vision, and hope will be that the UBX1325, irregardless of what other anti-VEGF or other molecule you are using, you're not gonna get the outcomes better than what we have seen based on data from Lucentis. So I think this can be an add-on treatment. You know, by the time it's approved, you know, there's gonna be a bunch of aflibercept biosimilars, and then, of course, HD aflibercept and faricimab, and I would expect most of the patients that are gonna be, you know, treated will be on, you know, the latest generation of agents. So yeah, I mean, I think this can add on to anything, in my opinion, if the data pans out, because we are not improving vision outcomes for patients with the newer agents. Great. Thanks. Okay, I think with that, we're gonna wrap up the discussion. Part of this session will be around to take additional questions, and I'd just like to close by thanking you for being here. But of course, thanks to all our retina specialists for your valuable time and your insights. Thanks to you. Thank you. you. Thank you, guys.