Good morning, and welcome to the Unity Biotechnology UBX1325 update call. At this time, all attendees are in a listen-only mode. A question and answer session will follow the formal presentations. If you'd like to submit a question, you may do so by using the Q&A text box at the bottom of the webcast player or by emailing your questions to questions@lifesciadvisors.com. As a reminder, this call is being recorded and a replay will be made available on the Unity website following the conclusion of the event. I'd now like to turn the call over to Lynne Sullivan, Chief Financial Officer of Unity Biotechnology. Please go ahead, Lynn. Thanks. Good morning, thank you for joining Unity Biotechnology's conference call to review additional data from the phase II BEHOLD study of UBX1325 in patients with DME. We will also provide an update on our ongoing phase II ENVISION study, which has data reading out at the end of Q1. With me today on today's call is Anirvan Ghosh, the CEO of Unity Biotechnology, Jamie Dananberg, our Chief Medical Officer, and myself, Lynne Sullivan, the Chief Financial Officer. Unfortunately, Dr. Bhisitkul is unable to join us this morning as he fractured his elbow skiing this weekend. Before turning the call over to Anirvan, I'd like to remind you that during today's call, we'll be making some forward-looking statements which are subject to risks and uncertainties, including those described in our latest 10-Q filed with the SEC. Actual results may differ materially from today's forward-looking statements, and we don't assume any obligation or intent to update them except as required by law. With that, I'll hand it over to Anirvan to start the discussion. Thank you, Lynne, and welcome to the UBX1325 update call. I will start off by providing an overview of our phase II studies of UBX1325 in DME and AMD. I'll also review with you the therapeutic hypothesis and the proposed mechanism of action of this of this molecule. I'll then hand it to Jamie, who will review with you the latest data we have from the BEHOLD phase II study in patients with DME. Following which, I will review with you the design of the phase II ENVISION study in patients with AMD. After which, we'll have some time for Q&A. We're exploring UBX1325 currently in two phase II studies as shown here. We have previously shared phase I data in both DME and AMD patients. I'll highlight that in the BEHOLD phase II study, we have previously shared up to 24 week data, and we're expecting 48 week efficacy data in the second quarter. In the ENVISION phase II study in patients with neovascular AMD, we are now expecting full 16 and 24 week data at the end of this quarter, and we're expecting 48 week data in the third quarter. The therapeutic hypothesis for UBX1325 in retinal diseases is shown in this slide. UBX1325 acts by a senolytic mechanism of action. It's driven by the disease hypothesis that during disease progression there is an accumulation of senescent cells in the vasculature of the eye, shown in blue in that inset. These are cells that are non-dividing, metabolically active cells that can secrete inflammatory factors that can lead to damage in the eye. They also form poor junctions with their neighboring cells, which can lead to vascular leak and eventually to loss of vision. In preclinical studies, we have found that elimination of senescent cells with a BCL-xL inhibitor, such as UBX1325, leads to restoration of vascular integrity, improvement of vascular flow, and improvement in retinal function. We're testing this hypothesis now in multiple clinical studies. I'll just go over a couple of key preclinical data sets that provide support for this mechanism. In this slide, we're seeing the impact of UBX1325 in animal models of diabetic eye disease. You can see that in this data set that a number of inflammatory factors such as IL-1 beta, IL-6 and TNF are upregulated in this disease model. With BCL-xL inhibition, there is a strong suppression of these factors. On the bottom right, we see the impact of BCL-xL inhibitors on vascular leak as measured by extracellular tissue albumin. You can see that in the disease model there's an increase in the amount of extracellular albumin, that is strongly suppressed with BCL-xL inhibitors, suggesting that BCL-xL inhibitors should both lead to a reduction in inflammation as well as a reduction in vascular leak. I'd also highlight that UBX1325 in preclinical models in neovascularization leads to both a reduction of neovascular growth as well as avascular areas. In the top half of this slide, we see that in the OIR disease model there is an increase in neovascular tufts that is strongly suppressed and replaced by healthy vasculature once treated with UBX1325. In the lower part of the slide, we see that there's an area near the fovea. Those dark areas are ischemic zones in this eye model, that those ischemic or avascular areas are significantly reduced in mice that have been treated with UBX1325. Based on these data and other studies, our proposed mechanism of action is shown in this slide. We believe that in the context of disease, there's an accumulation of senescent cells shown in blue on the left panel, those cells can secrete inflammatory factors and can lead to vascular leak. Following treatment with UBX1325, we expect that there would be a gradual elimination of the senescent cells, improvement in barrier function, reduction in inflammatory environment, eventually improvement in profusions through the blood vessels that should lead to improvement in vision. We're testing this in a number of clinical studies. We expect or to assess the potential differentiation of UBX1325 compared to current standard of care. This slide highlights some of the key areas of potential differentiation compared to aflibercept and for faricimab. We're targeting a profile for UBX1325 that would be efficacious in a broad patient population, including suboptimal and anti-VEGF responders. We are targeting a durability profile where at least 50% of the patients can go six months treatment-free. Based on preclinical data, we're interested in examining whether or not UBX1325 leads to improvement in vasculature and reduction in avascular areas of the eye. Our early data, both from clinical data and preclinical studies, support this emerging profile, and I'll hand it to Jamie to review the data we have in patients with DME. Thanks, Anirvan. It gives me great pleasure to share with you the data from the BEHOLD study in patients with diabetic macular edema. We'll be going over some of the data that we previously shared, but also some additional analysis to dive a little deeper into these data and provide some additional insights. As a reminder, the patients coming into this study were those who had been previously treated with anti-VEGF. The expectation on these patients is depicted in this slide with data from the VISTA study, one of the two registration studies for, which shows that the majority of benefit that patients achieve on their visual acuity is achieved in the first six months, first 24 weeks. You can see that once you hit around 24 weeks through, in this particular slide, two years, but the same is true as you continue on in these types of data, patients hit a plateau phase where they no longer gain additional visual acuity despite ongoing aflibercept treatment. As you can see, that second six months, which is blown up on the right, there's approximately one letter delta between the beginning of the second six months and the end of the second six months. Those are the approximate points in time when patients will be entering this study either here or even later, where the plateau phase is even more prominent. The design of this study, as I mentioned, the patients were required to have had at least two injections over the prior six months, coming into this study. As it turned out, the patients who we enrolled in BEHOLD had, on average, four injections over the prior six months, so an average of every six weeks. Despite that relatively heavy anti-VEGF burden, the patients in this study as they at baseline, had to have a residual retinal fluid of at least 300 microns and a visual acuity deficit of at least 73 letters or worse. As it turned out, their baseline retinal fluid was over 400 microns, and their baseline visual acuity was 61 letters. Finally, the patient's last injection had anti-VEGF injection had to occur at least three to six weeks prior to randomization. In effect, these patients are getting regular anti-VEGF injections on average every six weeks. At the time they would normally be getting that next injection, instead, they're randomized to receive either a single intravitreal dose of UBX1325 10 micrograms or a sham procedure, which is identical to the UBX injection procedure in every way except for the needle penetrating the eye. What we're gonna be digging deeper into today is the 24-week efficacy data that is depicted in the center of this. As Anirvan mentioned before, the 48-week long-term follow-up of these patients will come in the second quarter of this year. These are the BCVA data from the ongoing study through 24 weeks. Again, as you focus on the blue line, you'll notice that somewhere post eight weeks, these patients have this continuous improvement in visual acuity. On average, by the time we're at 24 weeks, these patients have gained 6.2 letters compared to where they were at baseline, which represents a 7.6 letter difference from the sham treated patients. As you can see, those patients from approximately two or four weeks, have this continual loss of visual acuity. You can see the statistical analysis in the top right where there's a high degree of statistical significance amongst these patients, between UBX and sham treated patients. This particular analysis avoids the confounding associated with anti-VEGF rescue, as all of the post anti-VEGF rescue data has been considered as part of this analysis and no longer, and not presented. As we dig into the data from these patients, we wanted to share what it looks like across the individual patients. These are the patients who were not rescued in the study. On the left are the sham patients, on the right are the UBX patients. We're looking from eight weeks onward, which is around the time when the patients settle in. Beyond the point at which there is perhaps a study effect which is demonstrated in ours and other studies. We're just looking at what happens when you get to eight weeks and beyond, as what is clearly depicted here in the sham patients. While there's a spread, you can see they basically distribute very evenly across the zero time point, suggesting there's really no ongoing benefit whatsoever to sham-treated patients. If anything, they are slow-- there's a slow downward trend overall. That's in contrast to the UBX-treated patients on the right where you see this continual improvement all the way from eight all the way through 24 weeks. You can see the vast majority of patients are well above the zero time points here, strongly indicating in our perspective, a pharmacologic benefit associated with UBX treatment in these patients, in the rescue-free patients. When we conducted an additional analysis that actually includes all of the post-rescue data. Whether patients had rescue or not, these data are all presented here. What you'll notice in the blue line is that the addition of anti-VEGF treatment to these patients provided no significant additional benefit. These patients still have approximately 6.4-letter gain compared to the previous graph, what had a 6.2-letter gain. The anti-VEGF did provide a small benefit to the sham-treated patients, but there's still a 5-letter difference between the UBX treatment and the sham treatment with high degrees of statistical significance. Again, demonstrating here that UBX provides a clinically meaningful and statistically significant benefit to these patients, even above and beyond anti-VEGF treatment. This is another additional analysis, just looking at the distribution of large gainers in this study. You can see that UBX1325 has a much higher proportion of patients who gained either 10 or 15 letters compared to sham. In fact, the sham-treated patients, there were no 15-letter gainers whatsoever. You can see as many as 12% of the UBX patients actually gained three lines or 15 letters or more on the ETDRS grid. The same is true whether you include rescue or not. Even in the presence of anti-VEGF, the UBX has an advantage compared to sham treatment. This is frankly an anticipated outcome given the fact that these patients had been on at the plateau phase of their treatment. Adding additional anti-VEGF treatment to those patients were not anticipated to provide them with a significant benefit, which is different from the UBX treatment. As we go to structure now, these are the CST changes. Again, these are the patients who were not rescued. This is not including post-rescue data. It includes all the patient data. What you see in the blue is stability of the UBX patients, which is in stark contrast to the patients who were treated with sham procedure, who gained retinal fluid throughout the course of this study. You can see that by week 24, the UBX patients maintained right at baseline, which represents approximately a 40-micron advantage compared to the sham-treated patients at week 24. When you include the anti-VEGF rescue back into this analysis, once again, just like in the BCVA analysis, the anti-VEGF did not provide additional benefit to patients, suggesting that UBX1325 stabilized the structure in a way that anti-VEGF did not further benefit these patients. However, the sham-treated patients did have some benefits, so there was no difference really at 24 weeks. Although UBX is still somewhat slightly better than the sham-treated patients of approximately 7 microns. Not statistically different. When we look at the proportion of patients who were rescue-free through 24 weeks, we see that fully 60% of the UBX-treated patients did not require anti-VEGF rescue. Again, this is in strong contrast to the sham-treated, the patients required rescue in the sham-treated patients. These are based on the rescue criteria listed below. We dug further into this analysis as well, and what you're seeing here is a swimmer plot. Each row on this plot represents an individual patient. UBX1325 treated patients are on the left, sham-treated patients are on the right. Rescue data demonstrates again, a likely pharmacological benefit associated with UBX1325 treatment in these, difficult to treat patients. In summary, in the BEHOLD study of UBX1325, it was well-tolerated. We had a favorable safety profile. There was no evidence of intraocular inflammation compared to sham-treated patients even without further intervention. With that, I'll turn it over to Anirvan to talk about some of the AMD work with 1325. Thank you, Jamie. We continue to be very pleased with the data we're seeing in patients with DME. As you saw that when you look at additional analysis at the level of individual patients, both on BCVA and rescues, the effect, the benefit of UBX is quite evident. Let me now turn to a discussion of the study in patients with AMD. This slide shows the senescence burden based on our analysis of human histopathological data in both sorry, DME and AMD. In DME, much of the senescence burden is in the retinal vascular layer in the more superficial layers, as shown here. In wet AMD, much of that burden is deeper in the choroidal vasculature layer. There is some difference in where the senescent cell sit in these two diseases. I do want to review with you the evidence of BCL-xL expression in neovascular growth. This is a slide shown from a preclinical OIR model that shows that in controlled retina, typically you see fairly low levels of BCL-xL expression. Whereas in the neovascular tufts, in the OIR model shown at the bottom right, you see high levels of BCL expression that's shown in the inset in green. We also know that UBX1325 is able to resolve neovascular growth in animal models. Here you see that in the OIR model again, there is a very effective resolution of neovascular growth in animals that are treated with UBX1325 compared to controls. These data then suggest that there is both expression of target at the site of pathology and that in preclinical models, we're able to resolve a key hallmark of AMD. I also want to review with you what we had previously shared from our phase I study that included both DME and AMD patients. That study was conducted in advanced AMD and DME patients who had been off of all anti-VEGF for at least three months. You can see that in the dose escalation period that there were, in the beginning, more DME patients than AMD patients. Based on that imbalance in the earlier cohorts, we had added a cohort of AMD-only patients at the 10 microgram dose, which is our phase II dose, so that we'd have a somewhat richer data set for AMD to determine potential benefit in that patient population. Here is the change in BCVA from baseline at the 10 microgram dose in all patients with AMD in that phase I study. What you'll notice is that following a single injection of UBX1325, we saw a pretty rapid improvement in BCVA that was then maintained out to 24 weeks. I'll note a couple things. There's one patient who had an outlier trajectory that's shown in the inset, had a pretty significant loss in vision, and after two rescues, had a reversal in the BCVA. It's not entirely clear because that patient's trajectory is very different from that of most other patients. It's possible that there is a small part of residual vision that allowed them to see greater letters at the final visit. All of the other patients followed the trajectory that's shown in the main graph. I also note that on the right-hand side is a summary of the patients who had rescue and when they were rescued. The physicians had considerable discretion in potentially treating the patients with anti-VEGF in this study. In the first 12 weeks, that data is entirely a UBX1325 effect. I'll note that although a number of patients received anti-VEGF between 12 and 24 weeks, the anti-VEGF did not affect the trajectory of these patients. We also assessed CST thickness, as shown over here in the AMD patients. You can see a gradual improvement in CST through the first 12 weeks that was then maintained through 24 weeks, suggesting that both in BCVA and CST measures in these advanced AMD patients, there was an evidence for signal of UBX1325. Looking at the images of patient eyes also supported that quantitative summary that I showed you a minute ago. This is an example of a patient who comes in with a fair bit of subretinal fluid and hyperreflective foci right in that vicinity, shown as those bright spots, which are associated with disease activity. Following treatment, going down to four, 12, and then 24 weeks, you see very nice resolution of the subretinal fluid, as well as a resolution of the hyperreflective foci, suggesting a potential benefit of UBX1325. This particular patient, you can see in the insets, have a significant improvement in CST, as shown in the bottom right, and had an improvement in BCVA over the 24-week period. Based on these data, we advanced this program to a phase II study, the ENVISION study in patients with AMD. I'll take a minute to review the patients who are coming into the study. This is the next major data readout that we have ahead of us. This is data taken from the VIEW 1 and VIEW 2 registration studies of aflibercept. Much like what Jamie shared with you, for DME patients who are treated with aflibercept reach a plateau somewhere between 16 and 24 weeks. Beyond the 24 week period, stay within about a letter of vision, even with continuous anti-VEGF treatment, as shown and expanded on the right-hand side. In our case, we're interested in asking that following an injection of UBX1325, can we alter the trajectory of those patients? The design of this study is summarized over here. This study has two parts, a part A and part B. The part A study will read out at the 24-week point, which is coming up fairly soon. The first part of the study is a head-to-head comparison of UBX1325 versus standard regimen aflibercept. The patients come in after having had anti-VEGF for at least six months, as it was the case with the DME patients. As in that study, these are patients who still have visual acuity deficits and subretinal or intraretinal fluid. When they come into the study, they first get a baseline aflibercept injection, as shown, or as Lynne is pointing, about four to eight weeks before being randomized. This is because patients can be on a number of different anti-VEGFs in the pre-randomization period. We wanted to make sure that there was no effect of a switch to aflibercept that could lead to a potential signal in that arm. Once they've had that baseline aflibercept, they get randomized either to an aflibercept arm or a UBX arm. On the UBX arm, they will get two injections of UBX1325 separated by four weeks, and then we'll follow them out to 24 weeks. In the aflibercept arm, they will receive every eight week aflibercept injection per normal protocol. This will allow us to assess at the 24 week period whether or not UBX1325 meets a non-inferiority margin compared to aflibercept, and whether or not we see evidence of a durability benefit. In part B of the study, we wanted to examine two things. One is whether a repeat cycle of UBX1325 allows us to maintain or maybe further gain on the treatment effect of UBX1325. That'll happen starting at week 24. The two injections, again, separated by four weeks. I will follow the patients out all the way to 48 weeks. We wanted to ask whether UBX1325 could provide an add-on benefit to the aflibercept arm, and that is shown on the bottom right, where beginning at 24 weeks, they get two cycles of aflibercept followed by UBX1325. This happens at the same patient visit. They get an injection of aflibercept, they wait for 30 minutes, and in the same visit, the physician then gives them an injection of UBX1325. We'll follow those patients out to 48 weeks to see whether or not when we compare that B2 arm with A2, whether we can see an evidence of a benefit of UBX on top of aflibercept. I'll note that many patients have already rolled over into the extension phase or part B of the study. So far, the experience of doing the dual injections has been positive and there have not been any issues. With that, I'll just wrap up with a summary of our upcoming data readouts. As Jamie summarized with you in the BEHOLD study, the next readout for that study is gonna be the 48-week readout, which we expect in the 2nd quarter. There, we're really going to try to understand the full durability benefit of UBX1325. As you saw that, you know, going from 18 to 24 weeks, there continued to be an increased separation between UBX and sham. As we go forward to 36 weeks and 48 weeks, we'll get a sense of how long that durability benefit might be, along with how long we see a separation compared to sham. In the AMD study, we're really excited about the upcoming data readout. We'll have 16 and 24 week efficacy data at the end of the quarter. Following that, we expect to have 48 week data, which is the part B of the study, in the third quarter. With that, I'm gonna hand the call over to Tara to moderate the Q&A session. Great. Thank you, Anirvan. To the audience, please hold while we pull for questions. Our first question comes from Yigal Nochomovitz from Citi. Please go ahead, Yigal. Oh, hi. Okay. Just curious, in terms of the expectations for AMD versus DME, is there anything about the mechanism that would suggest either, better or worse outcome? How are you thinking about the mechanism in terms of the way the disease process evolves for DME versus AMD? Thanks. Thanks for the question, Yigal. All of the preclinical data that we have in both diabetic disease models as well as neovascular disease models suggest that UBX1325 should be effective in targeting kind of the main pathologies associated with both DME and AMD. In AMD, kind of the main additional element that I highlighted that we'll be looking at is associated with, you know, neovascular growth that is a hallmark of disease. In preclinical models, we see good resolution of that. I'll just note that, you know, in those experiments, we had also done head-to-head experiments of UBX1325 with anti-VEGFs, with aflibercept, we saw very similar resolution in those side-by-side experiments of neovascular growth. That gives us reason to believe that it should have that effect in AMD. Other than that, there are many similarities in the two studies in terms of the patient populations that are coming in. We have some experience with this kind of patient population based on the DME study. The main difference, of course, in the AMD study is a head-to-head comparison with aflibercept. On the aflibercept arm, we really expect those patients to stay very close to, you know, no change from BCVA because they'll have had that baseline aflibercept injection before being randomized to that arm. And we'll really look to see first whether or not we see non-inferiority with UBX compared to aflibercept. Of course, the data set will also allow to see whether or not we see benefit, above and beyond aflibercept. In terms of the choice of Aflibercept, I guess that was just the obvious choice to compare it 'cause it's the market leader. Was there a different reason? No, the main reason for aflibercept is that I think that it is, you know, potentially, I would say, kind of the agent with which there's most experience and has been used as the head-to-head comparator in pivotal studies. We expect that as you move this program to pivotal studies, it would be a head-to-head comparison against aflibercept. We felt that generating that data in the phase II study would be valuable. If you show non-inferiority versus aflibercept, then or let's just say at a minimum, then the argument would be one of schedule and convenience. Is that correct? Is there more to the argument? Obviously, if you showed superiority, then that makes things even easier. If it's non-inferiority, what would be the argument for how you would do a phase III and, you know, the potential commercial angle? In the case of non-inferiority, you know, the comparator datasets, as you know, will really be what we have learned from faricimab and high-dose Eylea, which have given us a sense of the kind of durability one might expect. You know, with something like faricimab, you expect maybe about half the patients to go about four months. The two elements that we would look at in that case, if you're within that non-inferiority margin, the things we look at in the case where in the non-inferiority margin is gonna be, one, is durability, which is that what fraction of patients do we get to six months without additional dosing? As you know, in the DME study, we had about 60% of patients hitting that mark and something like that in AMD would be very impressive. The other is around evidence of potential disease modification. This is something we continue to be quite interested in, and we'll see whether or not we see evidence of disease modification, which might foreshadow what the long-term benefit might be compared to an agent like an anti-VEGF. Okay. would you ever consider some sort of a combo trial as well, or that's not the primary focus? Yeah. The combination part is, I think, a very important potential value proposition, in both indications. In the AMD study, we're gonna generate, kind of very relevant data in that part B of the study. That was entirely motivated by the idea that because it is an orthogonal mechanism, that we might get some added benefit of combining the two mechanisms. In my mind, in AMD, there are really a couple of ways in which there is a path to a strong product, and we'll see whether, you know, one or the other arm provides more compelling evidence. The first would be in the head-to-head monotherapy setting, do we see evidence of differentiation compared to aflibercept? In part B, we'll be able to see whether or not we see an add-on benefit of UBX1325 on top of aflibercept. Once we have those dataset, I think we'll have a sense as to where it is likely to provide the greatest benefit. I will point out one important thing about the AMD population that I think is sometimes missed when we really tend to focus on the first six months or first 12 months of registration studies. What is really striking and maybe an important unmet need in patients on anti-VEGF is that beyond the 1st year, and these have been tested in kind of long-term controlled clinical studies. Beyond the 1st year, AMD patients, even on anti-VEGF, will begin to lose vision. Their ability to maintain vision is not just driven by whether or not they're getting treatment. Even at one treatment, they start to lose vision. And you can imagine that over a five-year period after, you know, in AMD patients who are on anti-VEGF treatment, the beyond first year window is about 80%. 80% of AMD patients out there who've had anti-VEGF treatment are beyond the first year period. It's a very, very large population that on anti-VEGF are not benefiting and potentially losing vision. We see a, you know, big opportunity there in patients beyond that initial period. Of course, in addition to those who do not fully benefit during the first year, which is part of the inclusion criteria for our study. Okay. Thank you very much. You're welcome. Thanks for the questions, Yigal. Our next question comes from Salim Syed from Mizuho. Please go ahead, Salim. You're muted, Syed. Can you hear me now? Yeah. We can hear you. Okay. Thanks, guys. Thanks for the questions, guys, also wishing doctor the fullest speedy recovery. Hope he gets better fast. I guess a few from me if I can. One is for ENVISION. Can you just remind us how you're powered for non-inferiority at 24 weeks? How many letters difference actually communicate here that we actually are within the non-inferiority margin at 24 weeks. Will we have enough patients at the 24-week readout in March to actually fit within that powering since you've moved up the readout from second quarter to the first quarter? Salim, as of right now, we expect to have full 16 and 24 week data at the end of Q1, based on the kind of enrollment curves of the patients. I'll hand it to Jamie to comment on the non-inferiority margin for the study. For this study, we are powered to detect a non-inferiority margin of 4, minus 4 letters. That is actually a standard, Salim. If you look at the a whole series of studies that have been done recently, including faricimab, the 8 mg of aflibercept every 16 week data, those are all powered to their non-inferiority margin is set at minus 4 letters. That would be from the lower bound of the confidence interval of the data set that we have. We are powered for that, given our belief in the effect size associated with UBX in AMD patients. Okay. That's all. I think it's 51 patients, correct, Jamie? That's correct. Yes. All right. The second question is, just the relevance around the 16-week data at this point. Is there something in particular you're focused at for 16 weeks now that we're gonna be getting the 24-week readout? Yes. Salim, I think that now that we're gonna get a full 24-week readout, I think the 24-week assessment is of primary interest. The reason the intermediate points are important is that depending on the curve, the trajectory of BCVA, it can provide some insight as to, you know, when or whether one might need a repeat dose within that, within that period. In DME, as you saw, the effect continued to be quite strong at 18 and then onto 24-week. That is a different indication, and so in AMD, we don't know that yet. I think that the 16, 24 comparisons will give us a sense as to between 16 and 24, do patients stay relatively stable on their BCVA? They continue to improve or is there some sign of a waning effect? In this particular study, we will have the benefit of having a second cycle injection right after that, so that, even if there is some waning of effect between 16 and 24, we can then see that at 24. If I come in and give another UBX treatment, do I provide another round of benefit? Okay. The measurements are at zero, four, eight, 16, 24? When are you measuring the BCVA? Jamie, do you want to take this? Yeah, we have data every four weeks. Four weeks. The whole study, patients are being seen. That's correct. Just to add on to Anirvan's comment, Salim, you know, we're dealing with human populations, so one of the great interests for us is to look at the proportion of patients who are able to go rescue free for 16 weeks, for 24 weeks and beyond and early, because there's gonna be a distribution pattern. That'll help us define recommendations in the future for both pivotal studies and even out, you know, post-marketing about the best way to use a product like UBX1325. Having the sets of data longitudinally is very helpful. Okay. We're getting the actual curves when you get the data sets? Oh, yes. Via table with 16 and 24. No, no, no. We'll have the curve. Okay. Just, and just lastly, on the phase III design, just curious what the plans are now that you're gonna have 24 week data in hand. Do you have a meeting set with the FDA or do you need to wait for part B to finish before- Let me start that out, and then I'll hand it to Jamie to comment additionally. You know, the DME study is about six months or so ahead of the AMD study in terms of data readout. Our focus has been on kind of planning on what the next study in DME might look like. You know, pivotal study will certainly be informed by additional end-of-phase II interactions with the FDA. I will comment on one thing, which is that I think in the next study it is going to be important, it'll be, you know, for us to have head-to-head data with aflibercept. That is probably also the key feature that we're fully committed to. The rest of the design elements are still being refined. I think, Jamie, maybe you can at a high level comment on what we expect about maybe the patient populations who would go to the next study based on what we've learned. Yeah. I think, Salim, a couple points here to add on to Anirvan's comments. For sure, we will interact with the FDA to be able to highlight what we're gonna be doing in phase III. That is a planned interaction. But additional granularity we'll provide in the future on that. We want very much in the initial thoughts on our phase three to mirror closely what we have so far in our phase II program. We don't, as you might imagine, having surprises at that stage is not necessarily what we're looking for. We're looking for a benefit in patients who clearly need additional therapy. I mean, these patients are pretty much out of options at this point, so providing a benefit to this group of patients is of great interest to us. That doesn't mean in the future we won't explore broadened populations, but for now, we believe this group of patients is the one we're focused on centrally to begin with. Got it. Thanks so much, guys. Looking forward to the data. Great. Thanks, Salim. Thanks, Salim. Thanks for the question, Salim. Our next question comes from Andreas Argyrides from Wedbush. Please go ahead, Andreas. Yes, thanks for taking my questions here and appreciate the update. A couple for us. To start, can you just walk us through the patient population being studied in DME and by DME, in terms of disease severity? How long have they been receiving anti-VEGF? Not just for the past six months, but in total. I'll start there, and then I'll have a couple follows. Okay. Jamie, do you want to take the question? Yeah. the anti-VEGF treatment and- Yeah. criteria to enter the study? In the DME, I'll start with the DME population in BEHOLD first, Andreas. That population of patients have been on anti-VEGF for a minimum of six months. The historical data we have, it gets patchy when you get further back, as you can imagine. But all the patients we have entered into enroll in, that have been enrolled into BEHOLD have been treated for at least six months, many for one year and some for even longer, up to five years. In addition, all those patients are on a pretty substantial anti-VEGF burden. As I mentioned at the outset, the patients in BEHOLD have been getting on average, an anti-VEGF injection every six weeks. That's on average. Some are four, six or eight weeks at most, really. There's a pretty substantial anti-VEGF burden in these patients, and yet they still have pretty significant fluid and visual acuity deficits coming into this study. These are patients who are definitely in need of additional benefit from a product that's an orthogonal product to anti-VEGF like UBX1325. Now, as you move to ENVISION in the AMD study, those patients, that's a study that's still ongoing and is still fully masked. I don't have the full data set in terms of what those patients look like. The requirements from the study require them to have been receiving at least two injection of anti-VEGF over the past six months, much like BEHOLD. Though like BEHOLD, we anticipate that those patients may have a higher anti-VEGF burden than what is the minimum required in that study. Those patients also have to have some amount of fluid, either intra or subretinal fluid, as well as a visual acuity deficit of at least 73 letters or worse. All of these patients are kind of similar in that regard in terms of disease state. As you know, AMD is a bit more of an acute disease. We will, we are pulling together the data. At the time we release the 24-week data, we'll have a better feel for the actual distribution of patient treatment coming out. We'll disclose that at the right time in the future. Thanks, Jamie. If I can just add one more thing. I should just highlight, Andreas, that we have not seen any ENVISION study, just to kind of clarify, because we had previously kind of projected that we'd have 16-week data this quarter, kind of our, based on original projections of enrollment curves. As we got closer to the date, it became clear that we should be able to pull in the full 24-week data. We're very excited to be able to share the full data set. Just for clarification, we have not seen any ENVISION data. Okay, great. Just a follow-up to that question. You cut out a little bit, so maybe I missed it, Jamie. All patients are required to have fluid upon enrollment? Mm-hmm. Okay. Yes. In the AMD study, they all have some degree. It's not quantified like in DME in terms of Central Subfield Thickness size. In AMD, they all have to have some degree of intra or subretinal fluid as part of the protocol requirements. Okay, great. I know obviously, I guess the title of the call changed with Dr. Bhisitkul's accident. Hope he's well. How, you know, when might we get the... I guess, I presume we were gonna get some OCTA results from the phase II. To what extent are the preclinical retinal vascular data translatable to humans? How should we think about that? Yes, Andreas. You know, we are very interested in understanding the impact of UBX1325 on the vasculature because it's kinda core to both the therapeutic hypothesis and the preclinical data, as I've shared previously, show an impact on the vasculature. We are assessing this primarily using two measurements, FA and OCT angiography. You know, both, I would say, are relatively new in terms of use in clinical trials. We had highlighted those as being exploratory endpoints in our studies. As we were planning this call, we thought that we might have sufficient high-quality FA data to be able to make a comment on whether or not there's an effect. As we closer, got closer to the data set, it became quite clear that we, at this point, did not have enough high-quality FA images to draw definitive conclusions. We continue to collect both FA and OCTA data in these patients, and once we have robust data, then we would share it. That's kind of where it stands right now. In terms of translatability, I think that the main thing to highlight is that that feature of drop in vasculature in DME is seen in those animal models and is a hallmark of disease. You see these avascular areas or areas of capillary non-perfusion. An analysis will be focusing on that to see whether or not the effects we saw in preclinical models are also seen in our patients. We know from anti-VEGF studies that anti-VEGF agents do not affect areas of capillary non-perfusion, so there really isn't enough of a history to be able to speak to the question of translatability. In our case, it's a new mechanism, we'll continue to see whether we see an effect. The other main vascular pathologies, of course, neovascular tufts. There, overall, the translatability is positive in the sense that, you know, the approved agents, anti-VEGF agents that are in the market today, show impacts on neovascularization in preclinical models, and they show benefit in patients. In our case, we have evidence of similar effect on preclinical models, and we're awaiting data in patients. Okay. Last one for me. This is, you know, thinking a little bit farther out, but any thoughts on how the changing treatment landscape might impact potential phase III design? You know, thinking about Vabysmo and maybe Hydrosalia. Thanks. Yeah. I think for us, you know, the main thing to keep in mind here is that it's a novel mechanism of action, and therefore could provide benefit that goes above and beyond what anti-VEGFs provide. You know, starting with the current anti-VEGF like aflibercept and then VEGF-based mechanisms, like faricimab and of course, Hydrosalia, there isn't an expectation that those mechanisms would provide any additional benefit in terms of vision compared to aflibercept, and that has been what the data has shown. The argument there has been mainly around some benefit in durability, potentially. still a very significant significant fraction of patients don't get to about four to six months of inter-treatment interval. In our case, I think considering that as being the therapeutic landscape in which UBX enters, the main differentiation really is an orthogonal mechanism that could provide additional vision benefit compared to anti-VEGFs. The DME data, I think, quite compellingly shows that possibility. We're very excited about the possibility of providing additional benefit in DME patients. Of course, we'll see whether that is true in AMD. I think the AMD design also highlights the two different ways in which something like UBX could be successful, either as a monotherapy that is differentiated compared to anti-VEGF or something that could add benefit on top of an anti-VEGF. Okay. Great. Thanks, guys, for the insights. Thanks, Andreas. Thanks for the questions, Andreas. Our next question comes from Brandon Folkes from Cantor Fitzgerald. Please go ahead, Brandon. Hi. Thanks for taking the questions and for the presentation today. Maybe just one. Just diving into the non-inferiority in ENVISION and net margin. Given we're sort of relatively early here, though, but how do we think about where you fall in that non-inferiority margin? You know, and what I mean is, numerically a bit worse, does that change any hurdle rates for durability or some of these other aspects of the AMD product as we think about a commercial landscape versus just an approval? Let me start, then I'll kind of hand it to Jamie. I just want to kind of separate out maybe two elements of it. The first has to do with kind of a non-inferiority assessment that Jamie spoke to just a little while ago, which is defined based on a certain number of letters within kind of the comparator arm. In this case, it is a letter margin of four letters based on prior studies. Then the durability effect is not strictly embedded in that, but it's dependent on how far you go before you need to give them additional treatments. Just speaking to the durability arm and how we would be looking at it, right? We have patients coming in to ENVISION who will receive these injections at zero and four weeks, right. They're getting dosed a bit more than in the DME study. From that point forward, we will see how many how long can patients go before they need a potential rescue injection. The rescue criteria are quite similar to that in the DME study, which would be around a 75-micron gain in fluid or 10-letter drop in letters. We're gonna see what fraction of patients get to, you know, eight, 16, 24 weeks. The durability data will come from that and that will allow us to compare how that looks like compared to what has been previously reported with faricimab, for example. I don't know, Jamie, if you want to add anything to it or Brandon, if that answered your question, but happy to elaborate. Yeah. I don't, I don't have much else to add. I think you covered it all, Anirvan. I think, you know, I think the question you're asking is really based on the overall properties of what we see, which includes, where patients lie on the distribution, how long they can go without additional treatment, how well we're seeing an improvement in BCVA versus prevention of neovascular tufts or new neovascular lesions versus, fluid and stability. Yeah, I think that's, I think that covers it. Great. Thank you very much. Thanks for the questions, Brandon. I'll turn it back over to you, Anirvan, to address that one question. Yeah, we have a question in the chat from Matthew Caulfield. I'll just read it, then I'll address it. The question is at a high level, what is the best way to approach expectations for the 16 versus 24-week distinction in AMD? More specifically, do you anticipate potential durability differences compared to what we have observed in DME patients? As I think I mentioned earlier, the primary endpoint for the, you know, part of the study is the 24-week data set. We would really be quite focused on seeing whether we achieve our proof of concept criteria at the 24-week point. The 16-week data set, and frankly, even the earlier points, eight, 16, 24, will give us a better sense of the trajectory of change in vision. As in the DME case, it was very helpful to have those multiple data sets, data points to see how patients were changing over time. In the long term, that can influence a decision as to what a final treatment regimen might look like in terms of when we would need a repeat dose. We would have the same measures in this case at 16 and 24 weeks in terms of BCVA measures and CST measures. With regard to durability differences compared to DME, I would say that at this point, the really relevant data set we have is from that phase I study that I shared. It's a fairly limited number of advanced AMD patients. In that case, we saw that patients were able to, you know, maintain that initial improvement in vision at least pretty cleanly through 12 weeks. Between 12 and 24, patients had some level of intervention that did not significantly change their trajectory. Now, in that study, there were not strict criteria for when they would get rescued, whereas in this case, they would have to meet at least per protocol, the, those criteria to get an anti-VEGF treatment. We expect to have a kind of a more tightly controlled data set. I will point out one thing from the phase one analysis that we didn't share here today, but we have shared previously, is that we had looked at that data set to ask, you know, what fraction of patients went to different periods of time without hitting rescue criteria as opposed to when the patients were treated by their physician. In that study, in that analysis, we had seen that about 80% of the patients were able to go in that three to six month window without hitting rescue criteria. You know, that might provide some insight as to what we might expect. Of course, the real data we'll have next month will answer that question definitively. Great. Thank you, Anirvan. That concludes the question and answer session. I'll turn it back to you, Anirvan. All right. Thanks, Tara. Thanks, everyone, for all the questions. As you can see, we're very excited about the continuing strength of the DME data. I think it's quite robust. We're excited about the upcoming AMD readouts that we expect to have by the end of this quarter. Thank you again for joining the call.