Hi, everyone. Welcome back to Cowen's 41st Healthcare Conference. I am really excited to introduce Unity Biotechnology and Anirvan and Lynne on the management team. Thanks, Jordi. I'm happy to provide an update on Unity's platforms and programs. I'm Anirvan Ghosh, CEO of Unity, and we also have Lynne Sullivan, our CFO, on the call. Matthew, if you could forward a couple of slides, I'll give an overview of where Unity is. At Unity, we're developing therapies to slow, halt, or reverse diseases of aging. Our primary interests are in ophthalmology and neurology. In ophthalmology, we're focused on DME, diabetic retinopathy, and AMD. In neurology, a number of neurologic indications, including Alzheimer's, FTD, and PSP. The primary mechanism that we're targeting is cellular senescence, and I'll talk a little bit more about that in a minute. We also have programs that are based on other aging-related biology that we believe could have a significant impact on these diseases. Our goal is to develop transformative therapies that provide superior options to current therapies. If you go to the next slide. This just provides a summary of where our lead programs are. I mentioned that we are focused on ophthalmology and neurology. We have earlier-stage programs in a number of other disease areas. The lead program is UBX1325, which is a BCL-xL inhibitor, which is in a phase I SAD study in DME patients, and we expect to complete the safety study in the first half of this year. We also expect to start a proof of concept study in DME in the first half of the year and expect to generate significant data in the next 12 - 18 months. Behind that, we have a TIE2 agonistic monoclonal antibody program that targets vascular integrity in the eye for DME and AMD, and klotho, which is a biologics that has pro-cognitive activity. If you go to the next slide, it's a snapshot of the pipeline. The lead program is UBX1325. We have a backup that's not far behind, UBX1967, and I just mentioned the TIE2 and the klotho programs. If you go to the next slide, I want to take a minute to describe the senolytic senescence cell hypothesis and why we believe this could have a major effect on diseases of the eye and brain and other indications. What we know is that in the context of age-related diseases, there is an accumulation of cells that are dysfunctional. Often, they carry mutations that cause them to stop dividing, but they are still highly metabolically active. These cells are p16-positive and secrete a number of inflammatory factors collectively called the SASP, or senescence-associated secretory phenotype, and those factors are believed to lead to tissue damage and disease progression. Evidence that we have generated as well from the literature indicates that selective elimination of senescent cells can alter the production of these factors and alter the advancement of disease measures. The next slide shows the senolytic hypothesis. What we're aiming to do here is to see whether we can develop pharmacological agents that will allow us to selectively eliminate senescent cells, thereby eliminating the negative factors and restoring tissue health. I'll show you some examples from our eye program that are consistent with this hypothesis and approach. If you go to the next slide, I'm now going to spend a little bit of time talking about the ophthalmology programs, which are kind of the core to our pipeline. The lead program being 1325, a BCL-xL inhibitor. The next slide is a reminder of the key features of DME. As you know, DME is a severe aspect and complication of diabetes. It is a particular feature of a late-stage diabetic retinopathy where there is significant loss of vision, primarily because of effect on the foveal part of your eye, the part that gives you high acuity vision. In DME, what you see is a thickening of the macula, as shown in the images near the bottom right. You can see in a normal eye, there's a little bit of a dip in the macula. In DME patients, you see a thickening of the macula because of fluid accumulation that comes from leaky blood vessels, and that leads to loss of vision. It's a very severe disease. Patient progress pretty fast. It's a major complication of diabetic retinopathy. Our goal is to see if we can improve or reverse the course of that disease. If you go to the next slide, it summarizes the approaches that we're taking in this disease. There are two primary approaches. On one hand, we are targeting senescent cells that should reduce the inflammatory environment of the eye and thereby restore vision. The second approach shown on the right, and I'll touch upon it if I have time, is a way to activate the TIE2 signaling pathway that restores barrier function in vascular endothelial cells. If you go to the next slide, it is a overview of the current treatment options in DME and what we're looking to achieve with 1325. You know, the current leading treatment options in DME are anti-VEGFs. These have been very valuable drugs in the field, there's significant unmet need beyond anti-VEGF therapy. The standard of care involves either monthly dosing or dosing every other month, with the goal of reducing VEGF-induced neovascularization. Some patients respond quite well to this therapy, there are many patients who have suboptimal response. People either who do not show clear reduction in fluid in the eye, about a third of the patients really have no meaningful benefit from anti-VEGF. In addition, there is an element of ischemia in the eye in these diseases, anti-VEGF has no effect on reducing those ischemic regions, which eventually leads to neuronal loss and further decline in vision. With UBX1325, we're developing a molecule that we believe could provide rapid and durable effect after a single injection. Because the mechanisms will become clear why we might not need a repeat dosing or certainly not frequent repeat dosing. Our target profile would aim to seek dosing that is once every six months or less frequent. If you follow this field, you would know that that would represent a dramatic improvement in the therapeutic options for patients. There's a new mechanism of action. There are a lot of anti-VEGF derivatives being developed, but this has nothing to do with targeting anti-VEGF directly, and therefore, could act in combination with anti-VEGFs to provide greater efficacy, and could be a monotherapy alternative to anti-VEGFs going forward. Finally, one of the most exciting parts of the program is that we see the ability of this molecule to reduce ischemic regions and improve healthy vasculature in areas of the eye where there's been vascular dropout. There's a feature of disease that is not at all targeted by anti-VEGF that 1325 might be able to target. If you go to the next slide, it shows some of the evidence that motivated us to explore this mechanism of senescent cell biology. This slide shows that a number of inflammatory factors are elevated in eye diseases. This is in DR patients. You see an elevation of VEGF, shown at the bottom right. In addition, you see significant elevation of other factors such as PAI-1, IL-8, and IL-6. These factors are not targeted by anti-VEGFs and might explain why you have a lot of partial responders to anti-VEGF. These factors are also SASP factors that are generated by senolytic senescent cells, and we believe that targeting senescent cells might broadly affect these factors and lead to a greater impact on disease progression. The next slide provides a summary of some human data that shows accumulation of senescent cells in the context of disease. On the top left is quantification of senescent cell burden in AMD and DR/DME compared to age-matched individuals. On the top row, on the right-hand side, you see that in normal eyes, there's a very low senescent cell burden, shown in the teal color. On the right-hand side, in AMD, you see there's significant accumulation of senescent cells, both in AMD and in diabetic retinopathy. In the lower panel, we see that there is a close association with disease progression or disease activity, even within an eye. In this case, there is an accumulation of drusen in areas of active disease, shown in that little bump on the left. You can see on the right that in those areas where there's drusen accumulation, you see particularly high levels of senescent cells, whereas in areas away from drusen activity, you see less senescent cell burden. Not only is there an association with disease, that there's more senescent cell burden, within disease, there is close association with disease activity. These give us reason to believe that senescent cells might be driving part of this pathophysiology. The next slide goes into some key data that we've generated in animal models. Here we're looking at activity of UBX1325, which is a BCL-xL inhibitor that we have developed, and shows its activity on target and some key PK and specificity properties. On the left, we show a nice dose-dependent inhibition of BCL-xL activity. These data are generated in normal eyes. In normal eyes, you do not want to activate caspase, which is the downstream activator that eventually will lead to elimination of cells. Second panel, the mechanism of engagement panel shows that there is no increase in caspase activation in healthy eyes, which reduces the risk of safety-related events. You see the PK after a single dose, and you see significant inhibition of BCL-xL out to about 14 days. We know that the senolytic activity kicks in within a couple of days after injection, so providing sufficient exposure. On the extreme right, we see that the molecule is quite specific for BCL-xL, does not hit Bcl-2. In a paper that we recently published in Cell Metabolism that just came out a couple weeks ago, we describe the fact that it is the BCL-xL activity that's important and not Bcl-2, and reduces some of the liability of Bcl-2 inhibition. I'll also note that these are local intravitreal injections. Therefore, there's very low systemic exposure of BCL-xL, which gets away from some of the systemic liabilities of BCL-xL as a target. The next slide is an important slide that shows activity in a disease model. A disease model commonly used in this field is the oxygen-induced retinopathy, or the OIR model, that leads to high senescent cell burden and vascular leak and vascular dysfunction. On the top left, you see that you get inhibition of BCLXL in a dose-dependent way, both in the OIR eye and in normoxic eyes. On the bottom left, we see that despite similar levels of inhibition of BCL-xL, in the diseased eye, you get significant induction of caspase activation. In the normal eye, that is spared. There is a sensitivity of cells in a diseased eye that might allow senescent cells to be eliminated in that context, and one that you would not see in a normal eye. The consequences of that are shown in the quantification right next to it. In the middle panel, top, you see a very significant impact on reduction of neovascularization. You'll know that this is one of the key hallmarks of disease and one of the key measures that you look for in terms of drug activity in human studies. It shows that even at the lowest concentrations, we get significant reduction in neovascularization. Below that is the impact on avascular area that I alluded to, which is that we see a dose-dependent reduction in the avascular zone, suggesting that we are preserving healthy vasculature in larger parts of the eye. The right-hand panels show the images that correspond to that. On the top, you're seeing the disease model, where you see significant disruption of vasculature. You see that near the middle of the eye, there are many areas that look dark, where you have blood vessel dropout. These are avascular areas. At the bottom right, after a single dose of 1325, we see that there is significant improvement in vascular integrity. You can see healthy vasculature on the bottom right, and you can see that the dark areas in the eye have gone down significantly, indicating reduction in these ischemic regions. If you go to the next slide, it shows some comparator data with aflibercept, which is the leading anti-VEGF in the field. With anti-VEGF, you see a reduction in neovascularization as been reported previously, and you see no effect on the avascular area shown on the top right. On the bottom panel, along with a reduction in senescent cells shown on the bottom left, you see significant reduction in neovascularization, both with our lead molecule, 1325, and the backup, 1967. You see significant reduction in the avascular area shown on the bottom right. I also note that we find these effects even when you reduce senescence burden by about 20% or so. You do not need to completely clear senescent cells to be able to see these significant improvements. It's largely because we believe that the initial effect that you see are in the senescent cells in the vasculature. There are other senescent cells in the eye, but the vasculature senescent cells are likely to be the drivers of disease. The next slide shows that in addition to the impact on vasculature that I showed, there is an impact on vascular leak. Here again, we have comparator data with anti-VEGF. You see a strong impact with 13 25 in reducing vascular leak. Anti-VEGF data is shown as a final data point there. On the right-hand side, both anti-VEGF and 1325 lead to significant improvement in retinal function or photoreceptor function, as indicated by a-wave amplitude improvements. All of these measures indicate that 1325 has the potential to be a very important treatment option for patients with DME. With that in mind, we've initiated a clinical study. The next slide indicates the trial design. Right now, we are in an SAD study in DME patients who are quite severe. They have advanced disease. We're in a dose escalation study that will go up to five micrograms that will allow us to cross the predictive therapeutic dose. These patients will then be followed in a long-term follow-up. In all of these patients, along with safety measurements, we are measuring their visual function in terms of BCVA measures. We're measuring the thickness of their macula edema in terms of CST measures, as well as vascular leak as measured by fluorescein angiography. We expect to start a proof of concept study in the first half of the year, and the dose of that will be influenced by the phase I study. We expect to generate data, as I mentioned, in the next 12 -1 8 months, that will tell us something about the efficacy after a single injection of UBX1325. I'm now going to switch to the next program, which is our anti-TIE2 program. TIE2 is a molecule that is involved in regulating vascular integrity. The product vision is indicated in the next slide. Again, we're looking at a treatment option for DME and AMD patients. I already mentioned what we can achieve today with anti-VEGF. TIE2, again, is an independent mechanism, so it can act as a monotherapy or in combination with anti-VEGFs. It has the potential of superiority to anti-Ang2 mechanisms. I'll point out why. This is important because you might have followed that there's data that anti-Ang2, which as in the specific, can have some clinical benefit, but we believe that there's room for improvement beyond that. It has the potential, again, of improving healthy vasculature in areas where there's been ischemic drop. The next slide shows the signaling pathway engaged by TIE2. TIE2 is a receptor tyrosine kinase. The normal ligand is Ang1. The receptor is expressed highly in blood vessels, leads to activation of AKT and ERK, which regulates barrier function and reduces leakiness of blood vessels. In disease contexts, there is an elevation of another ligand called Ang2 that competes with Ang1 and can bind to TIE2. Because of its antagonistic activity, it reduces TIE2 signaling and is believed to be the cause of reduced vascular integrity and increased vascular leak. The next slide shows the activity of the molecule that we have developed. It's an agonistic Tie2 antibody, and here we're showing data in comparison with Ang1. On the left-hand side, in Western blots, you see tyrosine phosphorylation of the Tie2 receptor with Ang1 and downstream activation of phospho-AKT and phospho-ERK. On the right-hand side of that Western blot, you see that with a number of our Tie2 agonistic antibodies, we get strong receptor activation as well as downstream signaling. The right-hand dose response curves shows that we get very nice dose response with these drugs. With the different molecules that we're evaluating, we have molecules that give us comparable activity to Ang1, others that show stronger activity and others that show weaker activity. This is important because we are directly engaging Tie2 receptor and can regulate level of activation. I'll remind you that when you inhibit Ang2 as a mechanism, you're reliant on endogenous Ang1 levels, you're not directly manipulating Ang1 levels. Therefore, you might have significantly greater variability in the level of receptor activation that you get. The next slide shows one of the examples of data we have generated with regard to the impact of our TIE2 antibody on reducing vasoliteration, the loss of blood vessels in the healthy eye. On the left-hand side, on the bottom panels, you'll see a dose-dependent reduction in those regions where we have lost healthy blood vessels. The bottom right panels, again, you see compared to controls, you have significantly reduced those areas of the eye where you have had vascular drop-off. This is consistent with the idea that TIE2 signaling should preserve healthy vasculature and strong barrier function. I'm going to spend just a couple of minutes, to tell you a little bit about the neuro program. We're almost out of time. In neurology, we're interested in targeting senescent cells in neurologic disease. If you go to the next slide, it is a reminder that in neurologic indications, we see increased senescence burden in disease by particularly non-neuronal cells like microglial cells, which are known to drive inflammation in the brain. The next slide shows that we have evidence that by reducing senescent cell burden, we can significantly reduce a disease-related pathology. Here, maybe I'll just explain this, expand it a little bit. As you know, tau pathology is a key hallmark of a number of neurologic diseases, including Alzheimer's disease and FTD. In this case, we're looking at an FTD model mouse, the P301S tau model, which has an aggressive form of tauopathy, and that is indicated on the left-hand Western blots. You see significant increase in total tau levels, as well as phospho-tau, which is a form of tau that is found in tau aggregates. When we eliminate senescent cells, as shown on the right-hand side of those Western blots, you can see that we do not affect total tau, but significantly reduce phospho-tau and the insoluble fraction. On the right-hand side, you see those images showing that in this case, after elimination of senescent cells, you've largely, quite dramatically, reduced tau pathology. These are earlier-stage programs. As you know, there's a lot of interest in tau as a target, and I think it's quite impressive that in a non-tau-directed mechanism, we can get such significant effects. The next slide is a reminder that along with neurology and ophthalmology, we are active in a number of other disease areas, very early-stage programs. In each of these areas, cardiology, pulmonary disease, liver and kidney disease, and oncology, there's evidence of increased senescent cell burden. In many cases, we have evidence that the pathways we're targeting can also target senescent cells in other diseases. We believe that the work that we're doing in ophthalmology could open up large potential for this class of drugs, which would really be a completely new treatment option. With that, I'm going to just move forward and hand it to Lynne to just go over our financials. Thanks, Anirvan. Next slide. As of September 30th, we had $132 million of cash. That got us runway into mid-2022. Which also covers the funding for our proof of concept study in 1325. As Anirvan mentioned, we expect to have our phase I safety data in 1325 and DME in the first half of this year, and also we expect to start our proof of concept study in the first half of this year. Thanks, Lynne. With that, we are happy to address any questions that you guys might have. Of course, happy to follow up in other meetings. Thank you so much, Anirvan and Lynne. This was a great overview of some very differentiated programs going after significant opportunities. I guess before I open it up to investor questions through our online portal, I guess one question on my end is that obviously you focus on the pathological consequences of senescent cells, but could there be any benefits senescent cells provide? I guess that just plays into the question of what sort of side effects could you be worried about? Yeah, Jordi, a great question. Let me just provide some context about normal accumulation of senescent cells and what function they might serve, and the consequence of eliminating them. As I mentioned, these are dysfunctional cells, often carrying mutations. It is believed that the fact that there are senescent cells, that mechanism that provides cell cycle arrest might be a kind of an anti-oncogenic mechanism that prevents the cells to get into uncontrolled cell division. There is a mechanism so that you're preventing that risk. You're trying to keep it in that state. It is believed that those states might be pre-cancerous cells, an additional mutation that then lead to the risk of cancer. There really is no evidence that the senescent cells are serving a positive function, but it's a way of kind of checking the risk of cancer. If you eliminate it, obviously eliminate that risk, that would be the current hypothesis. Experimentally, we have also found that to be true, when we have eliminated senescent cells, the elimination of those cells were not seen to be associated with other pathologies or risks that might be of concern. One thing I will mention with regard to a therapeutic agent, BCL-xL as a systemic agent has some liabilities because there are other cells in the body that have a dependence on BCL-xL, which is why the local injection into areas is very important, so reducing systemic exposure. Other thing that's important is that since we're giving a single injection and then there's no more drug after that, it is like putting this disease in remission, right? You go in with a drug, you eliminate the senescent cells, restore healthy vasculature, and then you really do not have active disease process until maybe at some later point, there's some accumulation of senescent cells, but the process tends to be quite slow. That's kind of our current understanding. That's great. On the DME AMD program, you mentioned the benefit of reducing the dosing burden to patients. How long does it take for these senescent cells to replenish after elimination of your compound? Have you ever looked into this? Yes. In our experiments, typically, you get elimination of cells fairly quickly within the first week after dosing. It's a rapid elimination of cells. Normally, in the course of aging-related diseases, the accumulation is quite slow. It can accumulate over the course of years. After elimination, we would expect the accumulation of senescence to be relatively slow. We will find out exactly what the dosing regimen would need to be based on the POC study. Based on our modeling, et cetera, we believe that the possibility of once every six-month dosing or less frequent would be reasonable projection. Got it. That's great. I guess, what sort of glimpses of efficacy data should we expect to see later this year from the phase I DME study? How long would patients have been followed for? We are already following the patients that have been dosed, and we'll continue to follow them through the end of the year. We will have data that will go into several months for those patients. We'll have close to one-year data on the patients who are in the safety study. The patients that are in the POC study, which is expected to start before mid-year. We'll have at least six months data on those patients by the end of the year. In all of those cases, we are following their CST thickness, visual function, and vascular leak. Understood. With that, I do not see any additional questions in the queue. Thank you so much for accepting our invitation and joining us here at the virtual conference. Hopefully, next year it'll be in person. Thank you so much, Anirvan and Lynne for taking the time.