Good morning and welcome to the Unity Biotechnology Investor Call on the phase II clinical update in the BEHOLD study of UBX1325 in patients with diabetic macular edema. At this time, all attendees are in a listen-only mode. A Q&A 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, Lynne. Thanks, Tara. Good morning, and thank you for joining Unity Biotechnology's Conference Call to review 24-week data from the phase II 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, and myself, Lynne Sullivan, the Chief Financial Officer. We're fortunate to have Dr. Arshad Khanani, Director of Clinical Research at Sierra Eye Associates, 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-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 will turn the call over to Anirvan to start the discussion. Thank you, Lynne, and thanks for joining us on the call today. I'm pleased to share that based on complete analysis of 24-week data from all patients enrolled in the BEHOLD study, we see a strong, statistically significant, and clinically meaningful treatment effect of UBX1325 in patients with diabetic macular edema who are receiving suboptimal benefit from their current anti-VEGF treatment. Remarkably, the letter gains at 24 weeks after a single injection of UBX1325 are stronger than what we saw at 12 and 18 weeks, which provides very strong evidence of a sustained treatment benefit. I'd like to highlight that patients enrolled in this study had been on anti-VEGF treatment for at least six months, and on average were receiving one injection every six weeks prior to being randomized. Despite this intensive treatment regimen, these patients had visual acuity deficits and residual fluid in the retina. Patients were on anti-VEGF treatment until the start of the study. At that point, they were taken off of their anti-VEGF treatment and randomized to a UBX1325 or sham arm and followed for 24 weeks. Both patients and physicians were masked with regard to treatment arm. Let me now turn to the top-line results. A single dose of UBX1325 led to a progressive, statistically significant, and clinically relevant improvement in vision as measured by BCVA out to 24 weeks. Retinal structure, as measured by CST, was maintained through 24 weeks in UBX1325-treated patients compared to worsening of CST in sham-treated patients. UBX1325 showed a robust durability effect. Approximately 60% of UBX1325 patients did not require anti-VEGF rescue through 24 weeks, compared to only about 38% of sham-treated patients. I would also like to highlight that UBX1325 had a favorable safety and tolerability profile with no evidence of intraocular inflammation. We find this data robust and compelling and believe that UBX1325 could benefit patients as monotherapy or in combination with anti-VEGF agents. As you'll hear from Dr. Khanani, the separation between UBX1325 and sham arms continuously increase from 12 - 24 weeks with no waning of letter gains in the UBX1325 arm, strongly suggestive of a disease-modifying effect. Achieving such remarkable efficacy in a hard-to-treat patient population is a major validation of the senolytic therapeutic hypothesis and suggests that senolytic agents could achieve therapeutic outcomes that may not be possible with current treatments. It is worth briefly reviewing the senolytic therapeutic hypothesis as it is a novel mechanism of action and provides a framework for the sustained effects we see after a single dose. The potential benefit of senolytic agents in retinal diseases is motivated by the observation that there is an accumulation of senescent cells in the vasculature in both DME and AMD patients. These are non-dividing, metabolically active cells that secrete inflammatory factors that can damage the retina and lead to vascular leak. In preclinical models, we have found that elimination of senescent cells with BCL-xL inhibitors, such as UBX1325, leads to reduction in vascular leak, improvement in vascular anatomy, and improvement in retinal function. Based on these observations, we advanced UBX1325 to the clinic, and today we will be discussing the impact of UBX1325 in patients with DME. We believe that eliminating senescent cells leads to a remodeling of the vasculature, as illustrated here. In diabetic disease, we find evidence of an accumulation of senescent cells in the vasculature, as shown on the left. We believe that with a senolytic agent such as UBX1325, we can achieve a selective elimination of the senescent cells and a progressive remodeling of the vasculature that can restore vascular integrity and improve perfusion, which can lead to improvement in vision. Let me now turn to our clinical development plan. Today, we will be discussing the BEHOLD study data out to 24 weeks. We've added a long-term extension in the study, and we anticipate sharing up to 48-week data from this study in the second quarter of next year. There is an ongoing phase II study in neovascular AMD called ENVISION, and we expect to share data from that study in 2023. Before handing it over to Dr. Khanani to cover the clinical data, I would like to provide some context with regard to the patients enrolled in the study and what we would expect their trajectory to be under continued standard of care anti-VEGF therapy. In the BEHOLD study, we enrolled patients who had been on anti-VEGF for at least six months, at which point they were expected to have plateaued on the response to anti-VEGF treatment, as illustrated here in data from the phase III registration study of aflibercept. You will note that the improvement in vision with regular anti-VEGF treatment is primarily seen in the first six months, beyond which there is relatively little change in vision, as shown in the area boxed in red and expanded on the right. Visual acuity remains relatively unchanged after six months of anti-VEGF treatment despite every other month injection. In our study, we enrolled patients who would have been in that red box, take them off of anti-VEGF and ask if UBX1325 could allow them to gain letters above the anti-VEGF plateau. As Dr. Khanani will share with you, we see strong gains in visual acuity with UBX1325 during a period when they would not be expected to gain vision under standard of care treatment. With that, I would like to hand the call to Dr. Khanani to review the clinical data. Thank you, Anirvan. It's a pleasure to be here. I'm pleased to share with you and excited about presenting the first-time 24-week data from the phase II BEHOLD study in patients with DME. Before we dive into the data, let's look at the trial design. As Anirvan said, these are patients who actually had persistent DME even with treatment with anti-VEGF. Patients had to have residual fluid, 300 microns or greater, with a vision deficit of 73 letters or worse, despite having repeated anti-VEGF injections, greater than two injections over the last six months, and last injection had to be three to six weeks prior to randomization. Actually, most subjects in this study had three or more injections in the preceding six months. This is a patient population that we see a lot in our clinic. Many studies have shown that about 30%-40% of patients in our clinic receiving anti-VEGF therapy will fall into this patient population. Looking at the design, patients in this study were either randomized to receive UBX1325, a single injection or sham, and then they were followed over time based on disease activity criteria that receive rescue treatment. Today, I'll be presenting the data from 24 weeks, safety and efficacy. Looking at the endpoints, obviously this is a phase II proof of concept study. We are looking at safety and tolerability of UBX1325 in these patients. We're also looking at BCVA change from baseline, durability of response because a single injection of UBX1325, subretinal intraretinal fluid, CST changes, as well as patients requiring rescue, especially two or more rescue treatments. We have some exploratory analysis that we'll be doing in the future, including changes in choroidal blood flow using OCTA. In terms of patients enrolled in the study, you can see 32 patients in the UBX-treated group and 33 patients in the sham group. In this 24-week data analysis, we have a total of 59 patients. Now, let's look at efficacy. When you look at visual acuity, 24-week BCVA change from baseline met the pre-specified criteria for proof of concept. Here you can see patients treated with UBX1325 have sustained improvement over time, even till 24 weeks. You can see the visual acuity difference between UBX1325 and sham is 7.6 letters, and patients in the UBX1325 gain 6.2 letters. This is over a line of vision, and that's clinically meaningful for our patients. For example, if you have a young diabetic patient that works and is at 20/50 vision in the only good eye, if we can get them to 20/40 vision or better, they'll be able to drive and keep a driving license. Having over one line of visual acuity improvement is clinically meaningful for this patient population. You can look at the p-value. It was 0.0084. UBX1325 led to a sustained improvement in BCVA through 24 weeks. We also wanted to look at data from baseline, including post-rescue data. Again, what you see is improvement in visual acuity with a single injection of UBX1325. As you can see, patients treated with UBX1325, 6.4 letters here. There's some improvement in patients treated with sham, but again, the difference is 5.2 letters. UBX1325 with as-needed anti-VEGF rescue outperformed sham with as-needed rescue through 24 weeks. Again, highlighting the benefit of UBX1325 in this patient population with persistent DME. Looking at patients who gained two or three lines of vision, you can see that with or without rescue, greater proportions of patients in UBX1325 treated arm have larger visual acuity gains compared to sham at 24 weeks. If you look at three-line gainers, actually, there were none in the sham group, and there were patients in UBX1325 group that achieved three lines of visual acuity gains, again, showing the benefit of UBX1325 in this patient population. As a reminder, this is a patient population with persistent diabetic macular edema, even with frequent anti-VEGF injections. We wanted to make sure that we are looking at CST to see if we can stabilize disease. You can see here that in the BEHOLD study, 24-week CST change from baseline met pre-specified criteria for proof of concept. You can see patients who are treated with UBX1325 had stable CST compared to sham, where patients actually got worse. Here it confirms that UBX1325 is beneficial in terms of stabilizing anatomy compared to sham treatment. Looking at the post-rescue data, again, you can see there is some improvement in sham in CST after receiving the rescue treatment. We're going to show you the rescue percentages here, shortly, but where you can see that UBX1325 is still stabilizing the disease and adding anti-VEGF rescue improves CST in sham arm but not in UBX1325 arm. We also wanted to make sure that, looking at sub-population to see if UBX1325 is beneficial in certain subgroups compared to others. Here is a summary of the subgroup analysis at 24 weeks. You can see in BEHOLD, four subgroup factors with eight total subgroups were evaluated based on baseline values of BCVA, CST, DRSS score, as well as HbA1c. Here you can see for the response of BCVA, there was a numerical advantage in all 8 subgroups for UBX1325-treated patients. For the CST response, there was a numerical advantage in all 8 subgroups for UBX1325-treated patients, again confirming the value of UBX1325 in patients with persistent diabetic macular edema. Now let's look at rescue. You can see that majority of patients on UBX1325 were rescue-free for six months. In this study, rescue was based on CST, or visual acuity. This was not AN (uncertain). Either criteria meeting will trigger rescue. You can see 60% of patients treated with UBX1325 were rescue-free compared to 38% of patients in the sham group. Again, highlighting that UBX1325 is controlling disease, and we are not seeing worsening of BCVA or CST in majority of the patients. Again, this is with a single injection of UBX1325. Now it's a new treatment. It's a new mechanism of action, and safety is on top of mind for us, for a new agent. I'm happy to report that UBX1325 has a favorable safety profile. We have not seen any cases of intraocular inflammation, endophthalmitis, retinal artery occlusion, or vasculitis. You can see there were some ocular treatment-associated events, and these were all related to the injection procedure. Looking at the safety, it is very favorable, which is good news for this program going forward. Now let's look at some examples of images from the BEHOLD study. This is a patient that has actually been treated with five aflibercept injections over the last six months, and the last injection was four weeks prior to randomization in the BEHOLD study. Here you can see patient has very active disease at baseline. You can see intraretinal fluid. You can see subretinal fluid. Visual acuity was 68 letters and 423 microns in terms of CST. This patient received a single injection of UBX1325. As you can see, there is improvement over time, especially looking at 18 weeks after this single injection. You have significant gains in visual acuity and decrease in CST. At 24 weeks, the vision continues to improve. There is some reaccumulation of fluid, but overall, at 24 weeks, this patient gets 16 letters. That's over three lines of vision with a decrease in CST of minus 107, again, showing a very clinically meaningful response in visual acuity gain as well as improvement in CST. Looking at another patient. This is a patient treated with bevacizumab, four injections over the last six months, with the last injections three weeks prior to randomization. Again, at baseline, you can see this patient has very active disease with very poor vision of 35 letters and CST of 584 microns. As you can see, after a single injection of UBX1325, you see continuous improvement in anatomy. You see that large central cyst almost resolves with improvement in intraretinal fluid. You can see at 24 weeks, this patient has vision of 45 letters as well as CST of 300 microns. In this patient with chronic active DME, and again, we see many of these patients in our clinic, we have a gain of two lines of vision and -194 improvement in CST, again, showing a clinically meaningful response to a single injection of UBX1325. In both of these cases, no rescue was required. In conclusion, a single injection of UBX1325 provided evidence of a senolytic agent improving visual acuity in patients with persistent diabetic macular edema. To summarize the results of the BEHOLD study, UBX1325 was well-tolerated with a favorable safety profile and no cases of intraocular inflammation, endophthalmitis, retinal artery occlusion, or vasculitis. We have seen an improvement in visual acuity that was durable for a minimum of six months after one dose of UBX1325. UBX1325 treatment allows 60% of patients to avoid anti-VEGF treatment for at least six months in this study. UBX1325 maintained retinal structure versus sham-treated patients. I want to thank you for your attention, and I'm going to pass now to Jamie. Thanks, Arshad. We very much appreciate you sharing the BEHOLD data as well as your clinical experience with patients like this. That was a great summary of the data that we have observed in the BEHOLD study. It's important to remember that in the BEHOLD study data, that the 24-week data underscores the overall therapeutic potential for UBX1325. We were able to observe clinically relevant and statistically significant improvement in visual acuity compared to sham treated patients, while at the same time stabilizing the retina and controlling the disease based on the degree of stability of the macular edema as seen on OCT, and also quite remarkable improvements in retinal structure in some patients. These patients who have been on a high burden of anti-VEGF treatment, but just not getting improvement in their disease, meaning those injections were maintaining their status but not improving it. These data give us very strong impetus to put our efforts into the future program, and I'd like to take a minute and talk about that. On the timeline slide of our clinical program, we've completed the phase I study last year. That's in the top row. What you see in orange is the BEHOLD study, which we just shared the data from, the 24-week data that Arshad kindly shared. In approximately six months, we'll have the one-year readout from that study, and we're very much looking forward to see how these patients do over even a further extension of time. As a reminder, we also have the ENVISION study in wet AMD running in parallel. We anticipate the 16-week data from that study coming in Q1 of next year and the 24-week data in Q2. Downstream, we anticipate 48-week follow-up from the Part B portion of that study, and we've recently shared some of the design associated with Part B. The data you saw today has us very excited about planning and anticipating the pivotal program in DME, which is currently being developed. Our intention is to begin that study in the second half of next year with a readout as noted in here in 2025. We're very excited about that planning, and we're engaging with all of our stakeholders to make sure that that next study is of the highest quality and generates the kind of information necessary that we can bring this molecule to patients as quickly as we can. Patients are waiting. I've learned that over the years, and this is something that we're very excited about. With that, I will turn it back to Anirvan. Thank you, Jamie. Thank you, Arshad, for sharing the clinical data from the BEHOLD study. As you've seen today, we find compelling evidence suggesting that UBX1325 could provide vision benefit beyond what patients might achieve with anti-VEGF therapies, which has been the standard of care in the field for about 15 years. Based on a novel mechanism of action and the clinical data presented today, we find that UBX1325 can benefit patients who do not respond optimally to anti-VEGF therapy. We find that almost 60% of the patients can go without anti-VEGF treatment for at least six months, and they continue to gain vision. This level of durability has not been reported for other treatment options that are available to patients today. The disease-modifying potential of UBX1325 is supported by extensive preclinical data on remodeling of vasculature, as well as the sustained benefits that we see after a single injection. All of this suggests that we may be witnessing the emergence of senolytics as a new therapeutic concept that could set a new standard of care for progressive retinal diseases. I would like to close by thanking the physicians and patients who participated in our studies and who are helping us pioneer a new class of medicine. With that, we'd be happy to take questions. Thank you, Anirvan. At this time, we'll be conducting a Q&A session with our speakers. As a reminder, 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 @lifesc iadvisors.com. Our first question comes from Salim Syed from Mizuho. Please go ahead, Salim. Hey, guys. Congrats on the data. I apologize, I tried to turn on my video, but it looks like it's not letting me turn it on. I had a few questions, if I can. I think there was a line in the press release, and you guys sort of talked about it at the beginning of the presentation as well, about the patients that have dropped out of the study. I was curious if you can just speak to why have those patients dropped out, and the four patients that withdrew, when did they withdraw from the study, and how that data was exactly handled in the BCVA chart. Secondly, if you can confirm, I didn't see a baseline slide. If you can confirm that there were no baseline imbalances, that would be great. Just lastly, I know you guys are using mixed model repeated measures, but just for the heck of it, and I appreciate the time, but the rescue slide. Could you just maybe also characterize the time of the rescues, just generally when do those? Was there any particular time period when those rescues occurred? Thank you so much. All right, Salim. Let me moderate and remember each of the questions and direct them. The first question was around the number of patients who are in each arm, those that completed the 24-week visit, and what happened to the ones that did not. Jamie, I'll turn this to you to address first, and I'll get to the other ones. Yeah. Thanks, Anirvan. I'll do one at a time. Salim, the four patients in the UBX arm, two of them didn't drop out of the study at all. They just delayed their 24-week visit outside the visit window. In our statistical analysis plan, we explicitly highlighted that those patients would be excluded from analysis because they're too far out from their 24-week visit to consider that as actual 24-week data. Of the other two, one patient was just lost to follow-up. We couldn't identify where that patient was. The final patient just decided 24 weeks they had some other personal issue that they couldn't continue to stay in trial. That's the UBX side. On the sham side, one patient was just again lost to follow-up, and a final patient was associated with a site that had to close for their own personal reasons. Those are the six patients. Nothing out of the ordinary. We always plan for about 5% of sites, you know, patients and sites being an issue, 5%-10%. That's pretty typical. We're actually very happy with the ongoing enrollment of the whole study. It's been great, actually, and really good patient retention. I think, yeah, I'll just stop there. Okay, thanks, Jamie. Do you want to comment on the baseline characteristics and balance between the arms? Actually, it was very well-balanced, Salim. There was a slight difference in the baseline HbA1C between the groups, but actually it to the negative of UBX. That baseline HbA1c was part of the baseline covariate analysis for MMRM, so it actually takes that into account. But every other characteristic, baseline BCVA, everything we looked at, which is like a list of about 15 things, was very well-balanced throughout the study. We're really pleased with the balance in the study. Great. Thanks, Jamie. I'll take the other two parts, Salim. So, as you know, as we mentioned previously, the MMRM analysis is the kind of appropriate way to deal with data post-rescue so that the data that you saw is not gonna contaminated with rescue data. That's where we see the you know about 7.5 letter difference that Arshad highlighted. As you also saw in this case, we shared with you what the data looked like if you include the rescue treatment. Strikingly, even when you do that, you see a very significant over five letter difference between the two arms. I think we are very you know confident about the effects we're seeing of UBX1325 looking at it from multiple perspectives. You also asked a question about rescues. As you recall that at the 12-week point, the number of rescues between the two arms were similar. We had seen this increase in CST happening by that point and had anticipated it might lead to a rescue imbalance. In fact, that's what we see with about 60% going without rescue after six months, and the sham arm needing more rescues. We will be sharing additional details of the rescue, but I can comment on your question that we do see, generally speaking, both higher number of rescues and earlier rescues in sham compared to the UBX arm. Great. Thanks so much, guys. Congrats again on the data. Great. Thanks, Salim. Our next question comes from Yigal from Citi. Please go ahead, Yigal. Hi, Unity team. Thanks very much for taking the question. It's very interesting what's going on at the 24 weeks. We're seeing a continued improvement in UBX1325, albeit modest. We start to see the sham arm start to fall apart and drop below zero. Based on that, you know, just what are your sort of updated thoughts on the mechanism? Do you think that you're continuing to see removal of senescent cells at 24 weeks, or is this now more about the sham patients just really starting to under-perform with further removed from anti-VEGF therapy? Based on the data through 24 weeks, what are your thoughts on how you're thinking about the phase III and whether you think you might need a second dose, or given what we're starting to see here, whether one dose would be really sufficient to prove your point? Thanks. Thanks, Yigal. Let me start off, and then I might have Jamie comment a little bit on our initial thoughts on the pivotal study. With regard to the, you know, the timing of effect, as you pointed out, we see this continued separation between UBX and sham arms, between 24 and 48 weeks. Based on all of our preclinical data and what we have shared before, we believe that the senolytic activity of the agent happens fairly early in process, and that, following elimination of senescent cells, there's a gradual remodeling of the vasculature that allows it to, you know, restore vascular integrity and improve function. I think we're seeing that kind of long, sustained PD effect that outlasts maybe an initial senolytic action. The durability question is very interesting beyond six months. Of course, we're continuing to follow these patients, and we expect to have, you know, up to 48-week data as we go into the next couple of quarters. It is important to note that even at six months, we're not seeing a waning of the effect. So it is possible that you get really long, durable effects after a single injection. I do think that the data that we get from the 48-week data will allow us to better determine whether or not another injection at about six months might be valuable. We'll also be looking closely at the CST data. I think Arshad pointed out that, you know, the CST is maintained really well out to 24 weeks. In a couple of patient images, you can see there might be some sign of some fluid accumulation at six months, which might also suggest that a twice-a-year treatment might be a good way to kind of stabilize at that level. The sham arm, as you note, does seem to continue to worsen. As you see, that they're requiring quite a bit of rescue treatment. We expect that will probably continue, at least in that arm, that they will continue to get periodic anti-VEGF just to maintain. As a reminder, that is kind of where they started. You know, in the six months prior to data prior to being randomized, they had been on anti-VEGFs and were essentially kind of roughly maintaining CST and not improving vision. That is most likely the trajectory of the sham patients. With that, I'm going to hand it to Jamie to comment a little bit about how we are thinking of the pivotal study design and what are some of the key things that we will need to be addressing there. Yeah. Thanks, Anirvan. Yigal, we are considering various options for the phase III. Obviously, we're still in strong planning mode of that program. It includes designs that allow us to explore whether additional injections of UBX would be of benefit to patients in DME. We're obviously doing that in the AMD study. As I mentioned previously, the ENVISION study in AMD, wet AMD, will read out in Q1, and that study includes additional injections. We'll have some learning of what repeat injections of UBX does from that work to help inform us. There are some options we have that are quite clever, actually, I think, that will help us really begin to lay the groundwork for what the pivotal program looks like and how this will be used clinically at the end of the day. We do intend to run a study that provides that kind of information so physicians like Arshad have flexibility in terms of what they do and how they do it, and that's what we're looking for. Thanks, Jamie. Arshad, since we have you here, I think I'd like to address one of the questions, a part of it to you as well, in terms of, you know, as you see this profile of the drug acting and, the effects we see at six months, you know, how would you be thinking about, how this might fit into treatment paradigm or what we might want to explore as we think about a pivotal study design? I think those are great questions, Anirvan, and I think the bottom line is that, as Jamie said, we need flexibility, as clinicians. Each patient is different, and the response we are seeing here is clearly very meaningful, as I said, in this patient population. I think going forward, you know, looking at UBX1325 as a monotherapy and also as a combination therapy so that we have patients who can benefit just from UBX1325, and then we have patients in our clinic right now currently that can benefit, by adding UBX1325 to their treatment regimen. I think if a therapy is safe and really doesn't have any, you know, safety issues, and it appears to have a very favorable safety profile, of course, we'll continue to learn in all the trials, then I think we should have an option to use it on as many patients as we can. Because, you know, visual acuity is super important to these patients, as I said, and I think the gains we are seeing now are clearly directing it to a disease modification, a novel mechanism of action role. If we can go beyond just what we get from anti-VEGF agents, I think it's gonna be very meaningful for our patients. Thanks, Arshad. Thanks, Yigal. I just had one other follow-up, if I may, quickly for Dr. Khanani. You mentioned disease modification, and I think also, Dr. Khanani, you mentioned that we're going to get some OCT angiography data to measure choroidal blood flow in the future. Not exactly sure when, but we're looking forward to that. Just the question is, you know, based on what we've seen so far in terms of the potential disease modification on BCVA and CST, what are your thoughts on what you would expect to see on OCT angiography? Would you expect to see changes relative to sham, and how would that solidify your view of the overall mechanism and potential for this drug? Thanks. Well, that's a great question, Yigal, and I think, OCTA is still a relatively new technology. You know, there is obviously learnings that are happening in the field, especially in patients with DME. Of preclinical models, of course, we have seen benefit of UBX1325, and Anirvan and Jamie can add more to it in terms of, you know, helping with diabetic ischemia. Now, you know, OCTA obviously is, and Jamie can tell you, not all sites may have OCTA, and we are learning as a field. So I think it will be good to find a biomarker on OCTA. Obviously, you know, other agents have not done that. If you find one, that's great to follow. If you don't find one, that doesn't mean that this agent is not working because we are clearly seeing the BCVA improvement. The reason I said disease modification is because it's unprecedented to have an agent that can benefit patients for six months. We know that senescent cells are involved in this disease, and getting rid of them leads to decrease in cytokines, you know, IL-6, VEGF, and all the other cytokines. I think what we are seeing here is that the benefit of this sustains over time. I think we continue to learn. Again, these are early days for this molecule and mechanism of action, but it's really exciting to see the data we are seeing at this point. Great. Thank you. Thank you, Yigal. Our next question comes from Andreas from Wedbush. Please go ahead, Andreas. Good morning, Unity team and Dr. Khanani. Thanks for taking our questions. Without biomarker data, are these data establishing a correlation between the elimination of senescent cells and BCVA improvement? I have a couple of follow-ups. Yeah. Well, let me start out and maybe just as a reminder for the entire audience over here. Our therapeutic hypothesis is that UBX1325 would lead to selective elimination of senescent cells that would eventually lead to improvement in vascular integrity and retinal function. That is largely based on preclinical data, where we find that with UBX1325 and similar agents, we do in fact, in those animal models, we can measure vascular leak. We see a reduction in vascular leak, and subsequently, we see an improvement in retinal function. I should also mention in those experiments, there's a very nice dose dependency in terms of relationship between elimination of senescent cells and improvement in these anatomical and functional parameters. That was the basis of us selecting the dose that went into the clinic, right? That is all based on that data set. As you know, in clinical studies, there is not a way by which one can detect senescent cells in patient eyes. We have to infer the effect by looking at the predicted effects of such an agent and whether we see those changes. It is consistent, both in kind of the response we're seeing, the impact that we see on CST, for example, because it is predicted that there should be a reduction, or if it should maintain or not worsen your fluid if you're not continuing to increase leak. As we talked about earlier, we are quite keen on examining kind of the vascular outputs such as OCT angiography and fluorescein angiography to see whether that can provide greater insight. Those are really quite exploratory analyses in the entire field. We'll see whether that gives us a better sense. So far, I would say that the effects we're seeing in the time course are very much consistent with what we had learned from our preclinical models. May I add one quick point? Of course, yeah. Thanks. This actually goes back to Yigal's question as well. There's other measures in the study that we will be analyzing in the coming months, including wide-field angiography. I think Anirvan just mentioned that to also look at vasculature, especially on the retinal circulation, because we know in diabetes there's often a prevalence of ischemic areas which may also be driving VEGF production in the rest of the retina. That's one of the other measures that's coming in. It's also important to note from all these comments, UBX1325 is still an investigational product, still an investigational agent, and so there's a lot that we'll be learning over the coming months to help us understand how best we will apply for marketing authorization in the future and how best it will be used. Just a follow-up for Dr. Khanani. Would you consider the durability demonstrated at 24 weeks as clinically meaningful? Could you compare or how do these results compare to agents such as faricimab? I think that's a really good question, Andreas. I think so to answer the first question, yes, the visual acuity improvement or a line of vision is clearly meaningful for our patients. As you can see, and as Anirvan said, there was some re-accumulation of fluid in some patients, the ones I saw, but you know showed you. Still very significant improvement in vision and improvement in CST in these patients. Of course, you know, faricimab is bispecific antibody, so VEGF and Ang-2. You know, we really don't have data from faricimab in this high-need patients. Obviously, we'll be generating real-world data from it, but we don't have a controlled trial looking at patients treated with faricimab. Even in the YOSEMITE and RHINE study, patients actually who were previously treated, which was a sub-study, had to have a washout. Here we are looking at patients who are very high need, requiring frequent injections. So that's number one. Number two, of course, as you know, in YOSEMITE and RHINE studies, patients had to be treated, the maximum treatment duration was four months, not six months. It's very hard to cross-trial compare and look at these agents because this is a different patient population. It's a different durability. I think, you know, here this study will give us guidance, as Anirvan and Jamie said, how to design the pivotal study. We'll have to figure out, you know, how many injections of UBX1325 we'll need but the durability we are seeing, at least at this point, is clinically meaningful. All right. Thank you, and congrats on the data. Thanks, Andreas. Thanks, Andreas. Our next question comes from Brandon Folkes from Cantor Fitzgerald. Please go ahead, Brandon. Hi. Thanks for taking my question, and congratulations on the data. Maybe just for Dr. Khanani, just following on from some of the earlier questions. If we look at the patients who did not require rescue medication, how would you treat them in practice? You know, I guess any benefit to adding an anti-VEGF in practice here? Would you look to maybe add UBX1325 every six months? Now, granted, obviously, putting you on the spot there because we don't have that data. Just, you know, in practice, how do we think about the anti-VEGF sparing or, you know, monotherapy versus dual therapy just with the data we have today? I think that's a really good question. Again, these patients were frequently treated, right? Majority of them were treated with every six weeks of anti-VEGF. That's essentially maximum treatment that we can do in real world. You know, we say four to six weeks, and patients, you know, show up four to six weeks and, you know, I am out for meetings or patients get sick or whatnot. I think what we are seeing here is clearly that the patients giving more anti-VEGF may not benefit these patients a lot. As you can see, you know, in the sham group, patients receive more rescue. Again, we still had a benefit of UBX1325, you know, in these patients. I think clinically we are gearing our treatment just based on OCT at this point. With this new mechanism of action, we may have to look at other biomarkers that we were discussing earlier, that adding more anti-VEGF to a UBX patient that's improving may or may not benefit them. Again, this has the potential to be monotherapy versus combination therapy. I think what we do is going forward, we'll have to figure out where do this agent best fit in. You know, improving anatomy and not vision, in these patients with UBX plus anti-VEGF versus UBX alone, we'll have to learn that. We don't have that data yet, but I don't think these patients would benefit a lot with adding anti-VEGF, at least these patients who are super high need. As you saw, the patient I showed, you know, got monthly aflibercept and a very aflibercept very closely to before getting into the study, and they had a very, persistent DME-looking, picture. I think we continue to learn together, but I think it's exciting to see that with a single injection of UBX1325, you are seeing the outcomes that you are seeing at this stage. Thanks, Arshad Khanani. Great. Thank you very much, and congratulations again to the Unity team. Thanks, Brandon. Thank you, Brandon. Lynne, it looks like that's all for the analyst questions, so I'll turn it over to you. You're on mute, Lynne. You're muted. We have no further questions, so I'll turn it to Anirvan for closing remarks. Thanks, Lynn. Thanks, everyone, for dialing in. I'll just summarize by saying that, you know, for us at Unity, this is a very exciting moment, really a kind of pivotal point in this program. We've been waiting for this 24-week data set for a long time, and I think the evidence, Dr. Khanani presented today, I think, paints a pretty compelling picture of, a new therapeutic, potential therapeutic option for patients as we move forward. You know, you saw that in patients who are not responding optimally to anti-VEGF, which is pretty much the only option they have right now, to be able to give them an additional five, six, seven letters of vision is really quite striking. In the sub-analysis, you saw their patients were gaining, you know, two lines or three lines or 10 letters, 15 letters. That is quite remarkable. We see patients with significant improvement in CST, that says that it is having an effect on retinal structure that could be very valuable. We are very excited about the possibility of being able to develop another agent that can help patients with DME and then hopefully with AMD as well. I look forward to sharing additional data from the DME studies in the months to come, as well as from our new vascular AMD study. Thank you for joining the call.