Good morning, and welcome to the Unity Biotechnology Conference Call and Webcast. At this time, all attendees are in a listen-only mode. A question- and- answer session will follow the formal presentations. 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, Lynne. Thanks, Sarah. Good morning, and thank you for joining Unity Biotechnology's conference call to review the 48-week data from our Phase 2 BEHOLD study of UBX1325 in patients with DME. With me on today's call is Anirvan Ghosh, the CEO of Unity Biotechnology, Jamie Dananberg, our Chief Medical Officer, Mike Sapieha, our Chief Scientist, and myself, Lynne Sullivan, the Chief Financial Officer. We are fortunate to have Dr. Robert Bhisitkul, Professor of Ophthalmology and Director of the Retina Fellowship at the University of California, San Francisco, joining us for today's webcast. 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-K 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. Welcome everyone on today's call. I'm pleased to share that we see strong evidence of efficacy and durability with UBX1325 in patients with DME out to 48 weeks. You can be one slide back, Lynne, for a second. You'll recall that we had previously shared 24- week data where we saw initial evidence of gains in vision and durable response to UBX1325 in patients who had been previously on anti-VEGF. You know that the standard of care treatment in DME involves multiple monthly injections of anti-VEGF, followed typically with every other month anti-VEGF injection. These patients are under heavy treatment burden, despite this, a lot of the patients do not get to optimum vision. In this study, we had enrolled patients who had been on anti-VEGF for at least six months and were receiving suboptimal benefit. We took those patients off of their anti-VEGF and randomized them to either a UBX1325 arm or a sham arm and followed them out now to 48 weeks. This is to test the senolytic therapeutic hypothesis, which predicts that you should get lasting benefit of clearing senescent cells. Hence, we had given these patients only a single injection of UBX1325 and then followed them out to 24 and then 48 weeks. The next slide shows you the top-line results. We find that following a single injection of UBX1325, patients had a significant improvement in BCVA, gaining above six letters out at 48 weeks, which represented about a five and a half letter difference from sham. Over 50% of the patients who were randomized to the UBX1325 arm did not require any anti-VEGF rescue through 48 weeks. There was more than a 30-week difference in the median time to rescue between the sham arm and the UBX1325 arm. These are remarkable durability results, considering this is a 48-week study. We continue to see an effect on CST. We had previously shared that we saw maintenance of CST out to 24 weeks. That has now continued all the way out to 48 weeks, whereas the sham patients continue to perform poorly such that they gain significant amount of fluid by the time they get to 48 weeks. The safety and tolerability of the drug continues to be very positive. There are no instances of intraocular inflammation. In totality, we find this a very compelling data set with multiple lines of evidence indicating a strong treatment benefit of UBX1325. Before handing the call over to Bob, I'm going to briefly review the senolytic therapeutic hypothesis and the clinical development plan, talk about the patients who came into the study, Dr. Bhisitkul will then cover the data from this readout. This slide illustrates the senolytic therapeutic hypothesis with regard to retinal diseases. Senescent cells are cells that accumulate in various tissues, in this case, shown on the left in the vasculature of the retina, shown in blue. These cells are non-dividing, metabolically active cells that can secrete inflammatory factors and do not form tight junctions with their neighboring healthy endothelial cells. That can lead to vascular leak and fluid accumulation. In preclinical models, we have found that elimination of senescent cells with a Bcl-xL inhibitor, such as UBX1325, leads to the resolution of inflammation, improvement in barrier function, and improvement in retinal function in preclinical models. We predict that this should lead to improved visual outcomes in patients, which we're testing in multiple clinical studies. Here we show an overview of our clinical development plan. We have previously shared Phase 1 data of UBX1325 in patients with both DME and AMD. Following that, we initiated two studies, the BEHOLD Phase 2 study in DME patients and the ENVISION Phase 2 study in AMD patients. We have previously shared up to 24-week data from the BEHOLD study. Today we'll be discussing the 48-week data, patients having been on UBX1325 for almost a year. I wanted to comment on the patients who come into the study because this is an important element of the study design. We enrolled patients in the study who had been on an anti-VEGF for at least six months and were receiving suboptimal benefit from the standard of care. This slide, taken from the registration study of aflibercept, shows that most of the vision gain in DME patients happens over the first six months. Beyond that, there's relatively little change in visual acuity, even with continued treatment. Shown in the expanded plot on the right, you can see between weeks 24 and 48, for example, patients stay within about a letter of their incoming BCVA with every other month aflibercept injection. In our study, when we took patients off of their anti-VEGF, we gave them a single injection of UBX1325 and then followed them out for another 48 weeks, well beyond what's shown in this curve, to see whether or not we could provide them with benefit above and beyond what they're receiving with their anti-VEGF treatment. With that, I'll hand the call over to Dr. Bhisitkul to go through the primary data. Thank you, Anirvan, and thanks for the chance to talk about the BEHOLD Phase 2 study and the positive results that are seen with UBX1325 for patients with diabetic macular edema. Let's start by reviewing the Phase 2 study design here. These are patients that were included in the study that had diabetic macular edema, and this was previously treated diabetic macular edema that was fairly QT-prolonged and had a extended treatment course prior to entry into the study. This is shown by the inclusion criteria. These patients were required to have at least two previous injections of anti-VEGF over the prior six months. With the actual results showed that it was 4.1 injections for these patients overall over six months. That turns out to be about every six weeks injection of anti-VEGF, which we consider still in the heavy ongoing phase of treatment with anti-VEGF for these patients. Despite this heavy treatment, the patients had to have residual retinal fluid and macular thickening. They were required to be over 300 microns, and again, in actuality, it was about 440 microns on average for these patients. Fairly severe diabetic macular edema. Again, despite the heavy treatment, these patients had visual deficits. They had to be worse than 73 ETDRS letters. Again, in actuality, these patients on average were at about 61 letters. This translates to about a 20/63 Snellen vision. Again, pretty reduced vision for these patients. Let's review the study design shown here. Again, these patients have been receiving ongoing anti-VEGF, and I'll show you later on some of them for a year or two years or more. They were required to receive an anti-VEGF injection three to six months prior to entry into the study. Three to six weeks. Three to six weeks prior to entry into the study. At randomization, about the time that they would have been receiving an anti-VEGF injection in their ongoing treatment, they're randomized to receive either a single intravitreal injection of UBX1325 or a sham injection. I'll point out that for the remainder of the study, 48 weeks, there is no on-protocol anti-VEGF for either of these arms. All right. Rescue anti-VEGF, of course, is given according to strict rescue criteria, which we'll discuss later. These patients are watched until they require the anti-VEGF therapy. The compliance of the study was good. There were patients that only completed the first 24 weeks of the study as planned, that didn't roll over into the second 24 weeks of the study. There were some patients that dropped out for other reasons. Overall, good compliance of the patients remaining in the study to the end. Looking at the baseline characteristics, these were well-balanced between the sham arm and the UBX1325 arm, particularly in terms of visual acuity, in terms of central subfield thickness, and even in terms of the number of prior anti-VEGF injections they had and the specific drugs that they were receiving. Most of the patients were receiving either aflibercept or bevacizumab. Important for balance between these two was the chronicity of the disease. These patients had three years in the sham arm of existing diabetic macular edema. Again, fairly chronic disease and 3.5 years in the UBX1325 arm. We can switch to the key results. This is showing one way of looking at the durability of a single injection of UBX1325. This is a Kaplan-Meier curve. It's showing the UBX-treated patients in blue. The analysis is looking at the time to the first anti-VEGF rescue, where they met those rescue criteria of worsening. The worsening criteria were either the letters, the patient losing 10 ETDRS letters or more, or the patient on OCT worsening their macular edema by 75 microns or more for the central subfield thickness. Looking at the Kaplan-Meier curve, each of these downward steps represents 1 patient requiring their first anti-VEGF rescue over the course of the study. All right. You can see for the sham arm, it's pretty much what you expect when you switch patients to as-needed anti-VEGF. There's a steady decline in the number of the patients who can continue the study without requiring rescue, so that by the end of the study, the sham arm, about 80% of the patients had required rescue at the end of a year. This will be important for us as we look at the visual acuity results, because as the study progresses, there are fewer and fewer patients available for the analysis due to the high rate of rescue in the sham arm. We'll look at the data in a number of different ways to distinguish the effects of UBX1325 from anti-VEGF rescue. Now let's look at the blue line. I'm sorry, go back one more. Well, let's look at the blue line. This is the UBX-treated patients, you can see it's favorable over the first six months. After the first six months and going into the second six months, very few of the patients will then go on to require their first anti-VEGF injection. At the end of the study, 53% of the patients required no anti-VEGF rescue at 48 weeks. This is a year after a single injection of UBX1325. These patients required no anti-VEGF rescue, this is a statistically significant difference from the sham arm. As we said, we'll look at the data in a number of ways, this is the key finding from the BEHOLD study. The UBX-treated patients had a visual acuity gain above baseline of 6.2 letters at 48 weeks. This is one year after a single UBX1325 injection. These patients had one line or more of visual acuity, and this is statistically significant. Also in clinical practice we consider something clinically meaningful for our patients if it's more than one letter or five letters, and so this meets that threshold and exceeds it, okay. You can see that the benefit of UBX1325 is sustained over the course of the study. It was statistically significant from baseline for most of the points, with an exception here at eight weeks and 32 weeks. This is in contrast to the gray arm that's shown to the gray arm, that is the sham arm, where these patients basically stayed around baseline so that there was no significant improvement in baseline at the end of 40, at the end of 48 weeks. It's also excluding all post-rescue data. This analysis is one way of looking at the data that excludes the post-rescue data from anti-VEGF. Here we can look independently at the UBX1325 effect. You can see that as the study progresses, because more and more patients are being taken out of the analysis because of anti-VEGF rescue, that's very low. There's some other ways to look at the findings as well. Here is an analysis that's last observation carried forward, this is analysis that allows us to look at all 32 patients in each arm through the study, okay. Wherever they either get anti-VEGF rescue or leave the study, we look at what their visual acuity benefit was at that time. Again, you can see for the blue line, it's relatively unaffected for the UBX arm. These patients still gain about a line of vision at one year after a single UBX1325 injection. Again, this is in contrast to the sham group, where the LOCF analysis shows a steady decline as we'd expect, so that they are not improved over baseline. You can see there's a trend to them being under the baseline. In the bar graph here on the right, you can see that there was a delta of 7.6 letters between the gains in visual acuity seen in the UBX arm compared to the slight loss in vision that's seen in the sham arm. Finally, another way to look at the data is to include all the post-rescue data. Even if a patient gets an anti-VEGF rescue, they're included in this analysis. For the blue line, you can see that it doesn't affect the UBX1325 results much. The patients still have over a line of visual acuity improvement at 48 weeks. Then as expected in the gray arm, in the sham arm, you can see that there's an effect here that's now visible from the anti-VEGF rescue, so that there is some improvement for this group above baseline that's seen out to 48 weeks. This is clinically significant improvement in the UBX arm compared to the baseline in this analysis as well. Looking at the results categorically, you can see that 50%, half of the patients, gained a line of vision at 48 weeks, okay. Again, going back to what Anirvan was saying, these patients are not naive patients that have not previously been treated. These patients are well along in their disease course, where we expect really a plateau in the benefits that can be had with treatment. Here instead, we see some surprisingly robust vision gains, okay? Half the patients gaining at least one line, which as I said, is what we consider clinically meaningful, and 23% of the patients gaining two lines of vision. All right? Even some patients that are gaining three lines of vision, again, in the context that they should be at the plateau phase. Each of these categories is favorable compared to the sham group. Now, we'll turn attention and look at the OCT results for UBX1325. Starting here with the sham group, it pretty much does what's expected when you switch from, when you switch to as-needed anti-VEGF. There's worsening of the OCT and the macular thickening here. Worsening is when it's above the line here in this analysis, so that at the end of the study at 48 weeks, the patients were declined compared to their baseline. In the sham group, we saw stability. I'm sorry. In the UBX1325 groups shown here in the blue line, we saw stability of the OCT, okay. In the later parts of the study, you can see that the blue line is below, so that this led to a -13, 14 micron improvement. Clearly, at least it's not worse than the baseline. These patients had good anatomic stability after a single UBX1325 injection out to one year after the treatment. This analysis was looking at it excluding the post-rescue data. Let's look at this analysis that includes the post-rescue data. That is, even if a patient has an anti-VEGF rescue, their data is included throughout in this analysis. Here, you can see that the anti-VEGF rescue does improve what we expect to see in the sham group. Okay? They come closer to being stable compared to baseline. Still a trend to being above the baseline with macular edema worsening in the sham group. This is in contrast to the UBX1325 group, where there's good stability of the OCT, a trend to it being beneath the baseline so that there were 24 microns improvement at the end of the study, but again, at least, clearly not worse than baseline out to 40-48 weeks. This is another of the striking findings of this study, okay? Shown here in blue are the number of patients that required any rescue during the one-year course of this study. This includes all 32 patients in each arm. In the UBX1325 arm, over half, 53% of their patients, went one year without any rescue. This is in contrast to the sham arm, where only 22 patients could make it one year throughout the study without requiring rescue. Here, you know, this is, you know, again, as a clinical retina specialist, this shows us that we're seeing something new, okay? The idea of patients with chronic DME that have been requiring heavy treatment and then giving them a single intravitreal injection of this novel agent with a novel mechanism and requiring no further treatments out to a year, this is something that we haven't seen in our practice, and we haven't seen with standard of care that we're using now. Again, it speaks possibly to the unique mechanism of UBX1325 for this significant difference. It's always important to look at the safety of the drug, UBX1325 had a favorable ocular safety profile. The number of adverse events were fairly well-balanced between the two arms. Many of them just associated with the well-recognized adverse events that we see with intravitreal injection. Importantly, especially for retina specialists, we're very attuned to whether the drug causes any inflammation in the eye or not. There were no events of intraocular inflammation in the UBX1325 arm, which is reassuring to us as retina specialists. In summary, the BEHOLD study showed a concordance of evidence that supports a treatment effect of UBX1325 for patients with diabetic macular edema. The key finding is there was an improvement of 6.2 letters from baseline after a single injection of UBX1325 out to 1 year in these patients that were in the plateau phase of their management. 50% or more of the patients had a rescue-free interval of at least 48 weeks. These patients, half of these patients could go a year without requiring any anti-VEGF injection after a single injection of UBX1325. This points to me that there is, there may be some potential for this agent to have disease modification for patients with diabetic macular edema. The retinal anatomy, the retinal structure was maintained throughout the duration of this study without the need for anti-VEGF rescue in half of the patients. There was a good safety profile with ocular tolerability for UBX1325. Importantly, we didn't see any signs of intraocular inflammation with UBX1325. UBX1325 may be an important future therapeutic option for patients with diabetic macular edema, and we're looking forward to seeing the developments of this drug for further clinical trials. With that, I will turn it back to Anirvan. Thank you, Bob. We can stay on the last slide for a second, Lynne. I just wanted to kind of, Lynne, I think we can go back one slide, the summary slide... I just wanted to kind of comment on what we find in this study and what the implications are for this drug and as we move forward. I think you'll share our enthusiasm, and many of you have been following this story for quite a while, about the potential benefit of a senolytic agent such as UBX1325 in patients with DME. We had seen previously that by six months, there were significant letter gains after a single injection. Now with patients going almost a year and maintaining that gain is pretty remarkable. I think the part that I personally had not expected is the kind of durability we see in the second half with a, you know, sharp reduction in need for rescue treatments. Most of those rescues in the UBX arm happened in the first six months. It looks like once you get to that 6-month point, then, for many of the patients, you essentially become fully anti-VEGF rescue-free and can go the duration. You know, the study ends at 48 weeks, and for all we know, these patients can probably continue to benefit without needing additional anti-VEGF rescue. It is also important that it is achieving control of CST. That's important because physicians will often treat patients because of gain in fluid. They're really trying to check disease progression, that's a marker that's easily available in the clinic. You can see that, compared to the sham patients who are really struggling to maintain their fluid, even when you add anti-VEGFs, you can see many of them are still hovering a bit above baseline. With UBX, you get tight control and that, you know, reduction in fluid accumulation above baseline probably is contributing to some extent to the reduction in the need for anti-VEGF in these patients. Bob alluded to the fact that. This could be an indication of disease-modifying therapy. We know that the molecule, small molecule, Bcl-xL inhibitor, stays in the retina. Based on our preclinical models, we would predict that it's in the retina for just about two weeks. You're looking at effects that are out a year after that injection. Clearly not a PK-driven effect. The lasting effect would be consistent with a potentially disease-modifying treatment, which we're very excited about. I mentioned the standard treatment with aflibercept, which has been the standard of care for a long time, where patients will typically require an injection every other month. In this particular case, the patients are getting an injection every six weeks, so they're really heavily treated. We're able to take them out to much longer duration compared to that. Even looking at the landscape of other programs that are developed for these patients, finding an agent that can provide both a gain in visual acuity and strong durability, we think is going to be of great value to physicians and patients. I believe sets us up well for a subsequent study to test UBX1325 against aflibercept. With that, I'd just like to thank all of our patients, physicians, everyone else who's been involved in the study, and we'd be happy to take questions. Great. Thank you, Anirvan. At this time, we'll be conducting our question and answer session. Please hold for a brief moment while we pull for questions. Our first question comes from Salim Syed from Mizuho. Please go ahead, Salim. Hey, guys. congrats on the data. Dr. Bhisitkul, good to see you again. I hope you recovered from your injury. I believe it's a ski injury, if I recall. Thank you. I have a few, if I can. The first, for Dr. Bhisitkul. Could you perhaps put this data into context versus the AMD data that we recently saw? Obviously, which that was a head-to-head versus aflibercept, where we didn't see the non-inferiority threshold being met. This one obviously is versus shams. It's a little bit different, just sort of how you're thinking about your confidence in DME in light of the AMD results that we saw. Second question is just on the slide that you have here on the data, including post rescue. At 24 weeks, we saw the arms diverge from each other. Again, this was on the MMRM, based on MMRM analysis. I would have thought here that if, you know, based on MMRM, if you're including rescue here, you know, you would be accounting for the true change versus sham. We're seeing those arms now come in. Just curious how you're thinking about that. Again, this is not versus aflibercept versus sham. Just curious how you're thinking about why we didn't see that blue line tick a little bit higher, given it's including post rescue data. Just last... Just one more question, and then I'll, and then I'll stop. Make a note. I'll ask emcee to make sure all the questions get answered. Oh. The last question. Yeah. Yeah. This is the last question just on the Phase 2b, and maybe, I don't know, maybe this is, maybe this is for you, Anirvan. On the Phase 2b study that you plan on running here versus aflibercept. Just curious how you're thinking about how you're gonna manage that run-in period so that we don't run into a similar issue that we saw with AMD, where patients continue to benefit from anti-VEGF therapy? All right. Well, thanks, Salim, for all those questions. Just so we'll go to the first question, and Bob, have you comment a little bit on the strength of the DME data, and maybe put in context compared to AMD. I know they're two very different indications, but perhaps you could comment on that. I know you saw the AMD data also in detail. But I think primarily the findings from the DME data and what it means is probably the most relevant thing. Yeah, that question of seeing the different results here with UBX1325, different protocol with UBX1325 in the AMD study, ENVISION versus the BEHOLD study in diabetic macular edema. I think one thing it points to is that these are different diseases, of course. In this senolytic hypothesis, you know, there will be a different site where the cells are senescent. I have looked carefully at that ENVISION data and still convinced that even though it didn't meet the non-inferiority criteria against aflibercept, I'm convinced that there is an unmistakable effect of UBX1325 with visual acuity and with OCT for patients with the more acute and the more severe disease of wet macular degeneration. I think that's one explanation there. How we'll use this drug in diabetic macular edema versus macular degeneration, you know, that's gonna be something that the clinical trials will help us to understand, and it's gonna be something that retina doctors in the real world doing, using their practice will also work out. How is this going to be used with our existing standard of care of anti-VEGF? Just to point out that the rescue in the BEHOLD study was that it could be any anti-VEGF. It wasn't necessarily aflibercept. The physicians were instructed to use the anti-VEGF drug the patients had been receiving prior to entry in the study, but really it was a physician discretion choice. If I can comment a little bit more on the AMD DME point, because I realized that there's an apparent difference certainly in the level of efficacy you can see in the two, and a couple of points I think are worth highlighting. In the DME study, you know, also coming in, all of the preclinical evidence much of it comes from diabetic models, right? We can have a much better understanding of the translation in that. In AMD, we're still learning. I think in AMD there are a few key things that came out of that study that are going to be important in designing a next study. You mentioned the run-in period, which is very important, as well as the fact that in there the duration of AMD, to our eyes clearly has an effect and matches with, you know, corresponds to senescence disease burden. With, you know, with this new approach, we're still kind of learning what the optimum patient group is, and in AMD, it's a fast progressing disease. We see accumulation of more senescence later on. We probably need to, you know, gear our treatments towards those patients. Whereas in DME, you see pretty broad efficacy. We looked at a number of subgroups, I should have just mentioned that parenthetically. We don't see any one subgroup driving the response. You see kind of broad response in patients who have had chronic diabetes for a long time. I think that maybe the questions regarding the MMRM, maybe Jamie and I can address a little bit, but I want to make sure that we're addressing the right question. The slide that's up here is the including post-rescue data, but Salim, maybe you can just clarify a little bit. Was your question on the excluding or including post-rescue and what- Yeah, This is the right slide. Just, yeah, obviously we're seeing the arms come in between 24 and 48 weeks, right? At 24 weeks, they were diverging from each other. Mm-hmm. You know, I would have thought the MMRM model here would have adjusted for any change, you know, for any benefit that we may have seen from any rescue data. Right? You know, it would essentially be showing the true delta between the two arms. Yeah. I mean, I think I'll just make a note here. You know, what's not shown over here in great granularity is exactly, for example, in the sham arm, exactly when those anti-VEGF rescues are happening. Just for us to keep in mind a little bit, right? Because essentially, when you look at the post-rescue data, those rescues are happening at various times within this, within this plot. What we had seen early on, as you can see, this big separation in the second half. The main effect you see, you don't see much of an effect on the UBX arm. I think you'll see that you see this gain being sustained and looks, you know, quite consistent with what you had seen before. Bob pointed out that if you look at the sham arm, it looks like there might be some effect of the anti-VEGFs accumulating between 24 and 48 weeks. They are accumulating a lot of anti-VEGF injections also during that time. It tells you not only the new ones who need an anti-VEGF, even the patients who have had prior anti-VEGF are getting more anti-VEGF, right? I think that there is a cumulative, like, heavy anti-VEGF treatment that's coming up on the sham arm. Our statistician commented that at that point, we're really almost comparing the rescue treatments versus UBX treatment. I think that's what we're seeing over here. The methodology is very tight, so there's no manipulation. Let me comment on the next study and a potential Phase 2b study against aflibercept. You know, our confidence in the aflibercept study is really driven by what we are seeing in this study and what we know from prior aflibercept studies. That's the information we have to go with. From prior aflibercept, I think the data are very, you know, well, you know, well accepted that you will kind of get pretty steady vision after the run-in period of aflibercept. Your point is 100% correct. In the study design, having an adequate multiple of aflibercept run-in is going to be very important so that you don't have any unexpected gain in the aflibercept arm. That's, like, one feature. We really do expect them to be right at baseline. Based on this data set, our expectation would be that you should see a gain in visual acuity in the UBX arm and of course, hopefully greater durability. That's how we are approaching in our initial thinking around the head-to-head. Thanks for your question, Salim. Great. Thanks so much, guys. I think I saw Jamie there. Jamie, it's good to see you as well. I know. We're all sitting in New Orleans in a somewhat old conference room because of ARVO. If you're around here, we'll see you in live meeting. I'm in New York. Thank you very much, guys. Thank you. Yeah. Take care. Thanks for the question, Saleem. Our next question comes from Carly Kenselaar from Citi. Please go ahead, Carly. Great. Hi, team. I'm on for Ygal Nochomovitz. Thank you for taking our questions. Congrats on the update. Couple questions from us. First, just curious if there were any similarities in terms of baseline characteristics of patients who were able to go the full 48 weeks without rescue in the UBX arm. I guess a similar question for sham. First, were you surprised that about 20% of patients were able to go the full 48 weeks without rescue? Anything you can say about the characteristics of those patients would be helpful. Thank you. Yeah. Thanks, Carly. we did look at various features, particularly that analysis as to whether there was anything that would be different between those patients who went, you know, 48 weeks versus not in the UBX arm, for example. There isn't a, you know, predictor baseline characteristics, characteristic, if you will. You saw that between the two arms, they're well-balanced. Then you see there is not a significant difference among patients who go different durations in the UBX arm. I think you will recall from the first, 24-week data that there are a number of rescues in the UBX arm that happened quite early. and many of them beyond that, this is important to note. Just went all the way without needing additional rescue. So, I don't have individual swim plots with us at this in this presentation, but worth noting that many of the patients who did have a rescue did not continue to need a lot of additional rescue. That early accumulation we had previously noted might be related to the time course of the UBX effect to kick in. You know, the visual acuity gains start at about, you know, somewhere around eight weeks. Our view is that, you know, this mechanism of kind of restoring vascular health, vascular flow, probably takes that amount of time. There's some patients early on end up needing a rescue, and that was certainly true in the UBX arm. Beyond that, the patients perform quite similarly, and there's not other, you know, baseline differences. With regard to the sham arm, this is in a very high accumulation of anti-VEGF over the course of 1 year. You mentioned that there are a few patients who, at least as of the 48 weeks, have not received an injection. As you can see from the overall trends of the Kaplan-Meier, and other analyses, that they are continuing to get worse. One might expect that they, at some point, would need a rescue. You know, the time at which they get rescues, of course, is shifted. The Kaplan-Meier shows that probably has to do with their overall rate of disease progression, right? I think within this population also, there's some there's more slowly progressing than faster progressing, and they probably hit that rescue threshold a bit early. Hopefully, that helps. Lynne, can you put up that Kaplan-Meier curve? Carly, the question you're asking is one that we ask as clinicians as well. You know, are there predictors that will when this is, you know, when if, when and if this is available in the real world, are there predictors that I can use at baseline for my patients? I think that's going to be something important to look at. Here we're looking at patients that are pretty recognizable. They have that chronic DME. They've had ongoing anti-VEGF injections for a year. This curve struck me that there might be a predictor here. Looking at the Kaplan-Meier curve for the UBX1325, you can see that it's favorable compared to sham through the first six months. The effect really separates after the first six months, where if you didn't receive an anti-VEGF injection rescue there, very low chance that you would then require an anti-VEGF injection over the ensuing six months. Maybe there is a predictor for me as a clinician. If my patient makes it out to six months, I can kind of consider them home free. I might be able to reduce the monitoring visits that they need and have a prognosis that those patients are going to be stable over the long term. Thanks, Bob. Great. That's super helpful. In terms of the design for the Phase 2b, first on the dosing frequency, based on the data you've seen here, would you consider a second injection, say at the 24-week time point, for example? Second, on the positioning, it sounds like the plan for the phase 2b is to enroll a similar population of patients who have been on anti-VEGF. Curious if you had also considered going into a newly diagnosed population. Thank you. Thanks, Carly. We're still very much in the design development phase of the Phase 2b study, and we'll share details as they become finalized. I think there are a couple of features that I can comment on related to your question. You'll recall that we have consistently kind of projected the idea of a twice-a-year treatment. We wanted to see whether, you know, half the patients or over half the patients could go six months, and we felt that an every 6-month treatment would be a very, you know, strong, attractive option for patients. From the data that we have seen so far, I would say that with high confidence that within every 6-month kind of interval, we should be able to achieve and maintain strong efficacy. That's your, you know, 24-week point that you alluded to. I do think that we should certainly be considering something along those lines, because we don't want to be in a world where we're, you know, risking losing a UBX effect, for example. Certainly with every six months, you still would have significant margin on the other side based on this data set. You know, a lot of the physicians have also called out the fact that maybe it would be useful to have another arm which is a bit more of a personal treatment interval arm, because if the patients don't need that much treatment, then why treat? Bob alluded to the fact that if you look at the 6-month data, at that point, you know, a very high fraction of patients, if they haven't gotten an injection this first six months, they will not need one in the next six months. There could be some design element that assesses them at six months and then determines when the next injection should be, potentially in a different arm. With regard to enrolling patients, we want to make sure that we continue to enroll patients both who are in need and where we have high confidence of providing benefits. Patients, as in this study, I think would be a very good patient population. In DME, about half the patients don't get to 20/40 vision, even after a significant amount of anti-VEGF treatment. It's a sizable population. There's nothing about the mechanism that would preclude eventually it being used very broadly. There's nothing about, you know, the prior anti-VEGF treatment that would affect the senescence disease hypothesis, for example. As we go into later studies, we would, we'll look to getting to naive patients as well. Great. Thank you for taking our questions. Really appreciate it. You're welcome, Carly. Thanks for the questions, Carly. Our next question comes from Caroline Palomeque from Wedbush. Please go ahead, Caroline. Good morning. This is Caroline on for Andreas. Just a few from us. How should we think about efficacy in terms of BCVA and CST? Is a six-letter gain in BCVA consistent with the 56- micron improvement in CST? Bob, I'll turn this to you. Like how should we think about efficacy when you're looking at BCVA gain, CST, and what is your assessment of what we see here? Yeah, Caroline, again, it alludes to what we talked about before of what's meaningful for our patients outside of the clinical trial. As I said, you know, we usually put the cutoff of what's clinically meaningful, four letters, five letters, okay, or more. The six letters that we're seeing here in the BEHOLD study is at or above that threshold. This is meaningful. As I said, it's a little bit surprising that it's this robust because it's not what we would expect from, for example, switching from one anti-VEGF agent to another anti-VEGF agent. I think part of your question also is, you know, for the past two decades we've had this mindset that is based on the anti-VEGF world, okay? Where anti-VEGFs really are drying agents. They make the macula dry. They don't even really suppress the angiogenesis in a disease like macular degeneration. They're primarily drying agents. We've gotten used to the OCT not tracking one to one. It doesn't do that, okay? We know there's not a clear correlation between OCT and vision, even with the anti-VEGF agents. Here, where we're seeing stabilization of the OCT with visual improvement, I think what it's telling us is that this agent, which, you know, the hypothesis is that it's a rejuvenating agent for the target tissue. We're seeing that this is more than just a drying agent, that it has other benefits for vision, okay? Outside of removing the fluid. That, you know, the company is talking about ways now to find biomarkers that might be able to detect those non-OCT benefits of this as well. Then again, part of the question is, you know, these patients again are at the plateau phase. They've been getting anti-VEGF for a year, two years, three years. They're sort of reaching what they're going to reach in terms of the drying that's possible from the anti-VEGF agent. Thanks, Bob. Okay. Great. Then just one follow-up from us. How do you see these data stacking up against other extended duration therapies, including faricimab? Let me take that. I mean, I think based on the published data that's out there, and, I think it's fair to look at durability compared to faricimab. It uses very similar rescue criteria, for example. And I think you'll find that this level of durability is certainly, you know, more favorable than what we have seen so far from that agent. It's, you know, noting that faricimab, of course, has gone through approval and is now launched, and so we'll have to see how our durability data evolves as we go to later stage studies and hopefully final approval. I would say the initial data set, in our eyes looks very favorable. I mean, one thing I'll mention, without going into specifics of other competing programs, is that many of the other programs do target a VEGF-like mechanism. Either it's a way to keep your anti-VEGF in the eye longer or are targeting something that's, you know, blocking downstream signaling from the VEGF receptor, for example, in the TKIs. In those studies, what is expected and what is seen is no evidence of any vision improvement compared to what they were getting previously with their anti-VEGF. So there the differentiation efficacy is really noteworthy because I think that while the durability are striking, and I think this catches one's eyes when you look at this data set, the thing that I would say is kind of unprecedented is to get another five, six letters of vision beyond whatever they're getting with their anti-VEGF. you know, based on those, we feel very optimistic about this molecule. Great. Thank you so much, congrats on the data. Thanks, Caroline. Thanks for the questions, Caroline. Our next question comes from Brandon Folkes from Cantor Fitzgerald. Please go ahead, Brandon. Hi. Thanks for taking my questions, and congratulations on the results. I just want to come back to the patient population. Maybe was there any difference in the sham arm results in terms of patients, in terms of the number of anti-VEGFs those patients in the sham arms received prior to enrollment? Along those lines, how should we think about the patient inclusion criteria in the Phase 2b compared to what we saw with these patients? I'll comment on the first one, and then maybe Jamie can comment about like, you know, including the future patients in future studies. We did look carefully at the prior burden of anti-VEGF treatment, and it's very well-balanced across multiple dimensions. Here you can see that with regard to whether they had aflibercept or Avastin is very well-balanced. This level of resolution we did not have when we were looking at the 24-week data, so I was very pleased to see this balance. We also looked at the, you know, frequency of injections that they had received in the prior six months, and that is also very well-balanced, getting about four injections prior six months. There's nothing, there's no imbalance that stands out in the sham patient population compared to the UBX. By all accounts, they're coming in with very similar prior anti-VEGF treatment. Maybe I'll hand it to Jamie to speak to how we're thinking about the treatment population going into the next study. Just one more add to that also, Brandon. When we looked at individual patients, the density of their prior treatment did not relate to the response that we saw. Even patients on high treatment burden or moderate treatment burden, still all responded pretty similarly. No difference there. When it comes to the future patients, I think, we're very focused on this particular population. It is an area of high unmet need, in our opinion, amongst patients in this category. These are patients who still have poor vision, and the anti-VEGF, despite a heavy burden, is not doing it for them. I think as time goes on, we will certainly consider other patient phenotypes as we move forward. As Anirvan had mentioned previously, even onto naive patients at some point, if we can do something get in front of their disease, that would be pretty awesome as well. I think we really want to stay pretty close to the population that we saw in this, in the BEHOLD study, in our next study. Thanks, Jamie. I think, Bob, you have commented on this previously, which is that while we might start in a clinical study with a tighter patient population, but in your mind, based on the mechanism, being able to get to them earlier, before the disease is as bad as it is for these patients might be valuable, right? Yes. So again, getting out of the anti-VEGF era, to a different mechanism, you know, if you're offering me, an agent that is sort of reorganizing the population of the retinal tissue, okay, it's getting rid of the sick diseased cells and replacing them, allowing the tissue to replace it with healthy cells. You know, it's really, almost a rejuvenation therapy. This is getting looking very far forward. You know, if it's an agent that can be injected once a year or twice a year, maybe we don't wait until the patients start going blind from diabetic macular edema. Maybe we find a way to identify the patients with background diabetic retinopathy, as we call it, to pick out the ones that are at risk to start losing their vision. That's when we start giving them this treatment that's going to reorganize the cellular composition of the retina. Again, that will be a different clinical trial. That will be for the future. For what's planned here, this is a good population. Previously treated DME patients with incomplete responses. It's a good population to identify an effect from the drug, as we've seen here in BEHOLD. Thank you, Bob. Thanks, Brandon. One follow-up, if I may, Anirvan, and I guess it's kind of twofold. I guess firstly, sort of how do we think about sort of your go-forward plan here, right? I think there's a lot of ways you mentioned kind of we can take dosing, we can kind of look at patient populations. Are you looking at perhaps sort of focusing on a narrower patient population? Well, I don't want to say narrower, but sort of a specific patient population and a specific dosing regimen, getting that approved and then maybe adding some of these additional trials on a post-approval basis? Or are you looking at sort of bringing this to market with as broad a label as you can get? Then maybe this probably goes hand in hand with that. Very good data up until now. Anything you see in here that surprised you from the approach of the senolytic cell hypothesis? I know we talked specifically about dosing, and I heard your comments earlier about sort of not commenting just yet, but just at a very high level and holistically, how should we think about the go forward? Thank you very much. Thanks, Brandon. you know, it would make sense. It would be our intent, obviously, to, you know, make this molecule or potential drug available to as many patients who might benefit. It is our expectation that it is going to benefit a very broad group of DME patients. We have not seen anything in all of our sub-analysis, et cetera, that would indicate that it would only work in a subpopulation of patients. So the eventual path, I believe, would target DME patients broadly. I think with regard to path to approval and getting to all of those patients, I think the next study that Jamie alluded to and that we're thinking of, you know, would be one that really gives us greater confidence using a head-to-head design against aflibercept, optimizing a patient population where we're seeing strong responses so that there aren't uncertain elements in that study. Hence, we're talking about taking a similar patient population in the next study. Now, I think to get to approval, we will need more than that study, we expect. I think at that point, an important consideration is whether we run, for example, we could run a parallel study in the next study where we have a patient population that's like this or one that includes naive patients. There have been study designs where people have enrolled both naive patients and previously treated patients. Those are things that we still need to optimize. We would aim to, you know, get the patients to a broad group of DME patients in the most expeditious way possible. I think with regard to the senolytic hypothesis, and if anything surprised me, I think that the part that I think I'd say really impressed me but is consistent with this, with this model is kind of this separation of curves you see and greater durability you see past about 18 weeks or so. We've talked about this idea of, you know, vascular remodeling, vascular health. The work that Mike and his group has done on, you know, growth of healthy vasculature into avascular areas of the eye, has all struck us as being potentially a mechanism that could lead to disease modification. You know, one cannot make such claims lightly, but I would say if you look at how the patients are behaving now, you know, beyond six months, it certainly seems to be shaping up in that way. For us, that's been very gratifying. Great. Thank you very much. Congratulations again. Thanks, Brandon. Great. Thank you for the questions, Brandon. This concludes our question and answer session for today. I'll now turn it back over to Anirvan for closing remarks. Thanks, Sarah. Thanks, everybody, for joining the call. You guys have been many of you have been following this program for a long, long time, and you've seen us move from, you know, pre-clinical data that gave us confidence to move it into the clinic. You know, the very first hint we had was in these very advanced patients who had been off of all anti-VEGF for more than three months. We had this aha moment even in those few patients. Bob was there in the very, very early days. I remember the first few patients and saying that looks like something is happening. I think at this point, we have come a long way from that, from those early Phase 1 patients. I remember one of the physicians had commented one of their patients was a dental assistant who came back after a few weeks and said, "You know, I think I can see my tools more clearly." That physician thought it'd be kind of impossible to see that kind of response early on. We all took that with a grain of salt, but I think at this point, we have a lot of confidence. I think there's a robust data set here, that I think in most people's eyes would be seen as compelling evidence that UBX1325 could provide great value to patients with DME, which is a devastating and progressive disease of vision loss in patients. Thank you for your interest, and thanks for joining the call, and look forward to updating you about future studies.