Good morning, and welcome to the Unity Biotechnology Investor Call. At this time, all participants are on a listen only mode. A Q&A session will follow the formal presentations. If you would like to submit a question, you may do so at any time throughout the webinar. Today's call will be recorded and a replay will be available on the Unity Biotechnology website. At this time, I would now like to turn the call over to your host, Lynne Sullivan, CFO of Unity Biotechnology. Please go ahead, Lynne. Good morning. Thank you for joining the Unity Biotechnology conference call to discuss the 12-week and 18-week results from our BEHOLD study, a phase 2 study of UBX1325 in patients with diabetic macular edema. I'm Lynne Sullivan, Chief Financial Officer of Unity Biotechnology. With me on today's call is renowned retinal specialist Robert Bhisitkul, Professor of Ophthalmology and Director of the Retina Fellowship at University of California, San Francisco. Anirvan Ghosh, the CEO of Unity Biotechnology, and Jamie Dananberg, the Chief Medical Officer of Unity Biotechnology. On today's call, Anirvan will begin with an overview of the senolytic therapeutic hypothesis for retinal diseases and our clinical development plan before handing it over to Dr. Bhisitkul to review the data results. Then Jamie will discuss our upcoming milestones in DME and AMD before handing it back to Anirvan for closing remarks. We'll wrap up with a Q&A. Before turning the call over to Anirvan, I'd like to remind you that during today's call, we'll be making 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 do not assume any obligation to update them except as required by law. With that, I'll turn the call over to Anirvan to start the discussion. Thank you, Lynne. Good morning and welcome to everyone joining us on the call today. This is an exciting day for Unity Biotechnology and an exciting day for innovative therapeutics for retinal disease. I am pleased to share that we have achieved strong proof of concept for a treatment effect of UBX1325 in patients with diabetic macular edema who are receiving sub-optimal benefit from their current anti-VEGF therapy. UBX1325 had a favorable safety and tolerability profile with no evidence of intraocular inflammation. A single dose of UBX1325 led to a progressive, statistically significant improvement in vision as measured by BCVA out to 18 weeks in DME patients. Retinal structure, as measured by CST, was maintained through 18 weeks in UBX1325-treated patients compared to worsening of CST in sham-treated patients. We find the data set robust and compelling and believe that UBX1325 could benefit patients as monotherapy or in combination with anti-VEGF agents. This is an important milestone for us as it is a validation of our senolytic therapeutic hypothesis that Unity was founded on. Because cellular senescence is associated with a broad range of age-related diseases, we believe that a senolytic approach could be relevant for a number of other indications. 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're seeing after a single dose. The potential benefit of senolytic agents in retinal disease 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 a selective elimination of senescent cells, improvement in the vasculature, 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. This slide provides an overview of our clinical development plan. We have previously shared phase 1 data of UBX1325 in both DME and AMD patients. Today, we'll be sharing data from our phase 2 BEHOLD study in DME patients out to 18 weeks, and we expect to have up to 24-week data by the end of the year. We have added a long-term extension to this study and expect to have up to 48-week data in the first half of 2023. We also have an ongoing study of UBX1325 in neovascular AMD. We expect up to 16-week data from that study by the end of the year and 24-week data in the Q1 of next year. Before handing it over to Bob 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 our study, we enrolled patients who had been on anti-VEGF for at least 6 months, at which point they were taken off anti-VEGF and randomized to either sham or UBX1325 treatment. The benchmark study in this field is the phase 3 registration study of Aflibercept. This slide shows the treatment effect of Aflibercept in the VISTA study. 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 boxed area in red and expanded to the right. Visual acuity remains relatively unchanged after six months of anti-VEGF treatment despite every other month injection. In our study, we give patients a single injection of UBX1325 and then follow their trajectory. As Bob will share shortly, we see strong evidence of improvement in visual acuity with UBX1325 during a period when they would not be expected to gain vision under standard care treatment. I would like to note an important difference in the study populations in our phase 1 and phase 2 studies. In the phase 1 study, we enrolled patients who had been off of all anti-VEGF for at least 3 months and were not expected to benefit from any anti-VEGF treatment. In contrast, in the phase 2 study, we enrolled patients who were under active anti-VEGF treatment and required anti-VEGF to manage their disease. These patients had been on an anti-VEGF for at least 6 months before enrolling in our study, and on average, had about 4 injections in the prior 6 months. Despite that fairly heavy treatment regimen, they had residual fluid and visual acuity deficits. At that point, they're taken off anti-VEGF and randomized either to a sham arm or a UBX1325 treatment arm. With that, I will hand it over to Bob Bhisitkul to go through the clinical data from the BEHOLD study. Thank you, Anirvan. What we'll discuss today is the results from the phase 2 BEHOLD study of UBX1325 for patients with diabetic macular edema. This is a 12-week interim analysis that was planned. Of course, the primary endpoint is a 24-week point, so this is the halfway point. It was found at the time of the data cutoff for analysis of the 12-week data that there was also a substantial number of patients, the large majority, that had completed the 18-week time point as well. I'll include both the 12-week and the 18-week time points in the presentation today. As Anirvan mentioned, this is patients with diabetic macular edema who have previously been treated with anti-VEGF. The inclusion criteria was that these patients had had at least 2 injections of anti-VEGF over the prior 6 months before entering the study. The data results actually showed that it was even higher than this, that it was on average 4 injections over the previous 6 months for these patients. They're really undergoing active, anti-VEGF therapy for their diabetic macular edema. About the time that these patients would have been receiving their next injection, they are then randomized into the study. Half of the patients, 32, received UBX1325 as a single injection on the first day of the study, and the other half received sham injection. That is for the standard sham protocol, the hub of the syringe is pressed against the eye, but of course with no needle injection. It should be pointed out that even with active anti-VEGF therapy, these are patients that still had some level of persistent diabetic macular edema, with residual retinal fluid and macular thickening at 300 microns or more on the OCT and visual acuity reduced to 73 letters. The BEHOLD endpoints are safety, visual acuity as measured by change in vision from baseline on with ETDRS letters, and then also the change from baseline in the level of the macular edema as measured on OCT with central subfield thickness. The primary datasets included 65 patients that had completed the 12-week time point, all of the patients in the study, and 54 of those patients who had completed the 18-week visit as well. That'll be included in this analysis. The analyses were performed by a mixed-model repeated-measures method. This is a widely used and accepted methodology. It's a way of analyzing longitudinal datasets. What it does is it effectively addresses post-rescue data so that the analyses that we see here today are not confounded by any effects of anti-VEGF rescue. Here are the results. This is the version of results, and this is showing the change in vision from baseline. I'll point out that the UBX group is shown in blue here, and the sham group is shown in gray. You can see that at 12 weeks, there is an increase in vision that is even further increased at 18 in the UBX group compared to the sham group, which remains relatively unchanged at these time points. The UBX group had gained 4.7 letters at week 12, and this was a difference from the sham of 3.4 letters with a p-value of 0.11. At week 18, this was even more pronounced. The UBX group had gained 6.1 letters with a difference of 5.0 letters from sham and a p-value of 0.03, which is robust comparable to that seen in a registration trial. Instead of seeing the maintenance of the plateau that Anirvan talked about at this stage of the treatment management, this group of UBX patients actually showed a one-line improvement on average from their baseline. Next, we'll look at the anatomic results on OCT. This is the change in baseline in the central subfield thickness or the CST. I'll just remind that for macular edema worsening, that's indicated by the line rising above on the graph. You can see that this is what happens with the sham group shown here in gray, that at week 12 and at week 18, there was an increase in the thickness or worsening of the diabetic macular edema. As opposed to this, the UBX group did not show any worsening of the diabetic macular edema at weeks 12 and 18, maintaining the macular thickness at about the baseline. This is shown at week 12, with the sham group having a worsening of 40 microns on the OCT CST, while the UBX group had a decrease of one letter. There was a difference of 41 microns in favor of UBX for a p-value of 0.07. By week 18, again, this was more pronounced. The sham group had then worsened by 53 microns, while the UBX group had a change of 3 microns. This is an advantage of 50 microns in favor of the UBX group with a p-value of 0.07. There was a congruence then of the change associated with UBX treatment in both the vision and the central subfield thickness. This is a proof of concept study of relatively small numbers of patients, and it's appropriate for this level of study for the power of the study to aim for a false positive rate of about 15%. In this way, p-values that are less than 0.15 are, for the purpose of this study, considered significant. At week 12, we see a directional movement of the advantage of UBX1325 for both vision and for central subfield thickness. It had an advantage over sham of 3.4 letters at week 12 for a p-value of 0.11. The CST showed this advantage of 41 microns on the OCT for a p-value of 0.07. Again, the same difference was carried through with congruence of the vision in the subfields thickness. The visual acuity difference then the advantage for UBX1325 was 5.0 letters, and this had a p-value of 0.03. The advantage on the OCT for central subfield thickness, UBX had a favorable differential of 50 microns here for a p-value of 0.07. In terms of rescue, and we'll look at some more of those data in the next slide, there was a greater use of rescue in the sham group than the UBX1325 group. The analysis that we've seen today has used the MMRM model to censor any effects that are involved with anti-VEGF rescue. Another analysis was performed that looked at the data after anti-VEGF rescue. As expected, this attenuated the differential benefit of UBX for vision, but had a much smaller impact on any differential for the central subfield thickness. The whole study performed a subgroup analysis here to look at varying factors that could be affecting the outcomes with UBX1325, and these are parameters such as vision, central subfield thickness, diabetic retinopathy severity score, and hemoglobin A1c. Dividing across each of these parameters into more severe or less severe. The goal of this was to determine whether there was a single factor that was driving the UBX1325 effect that was seen. There wasn't. There was a broad overall effect for UBX1325 across all of these groups. For the BCVA, across all of these eight subgroups, there was a numeric advantage for UBX1325 over sham. For central subfield thickness, seven out of the eight of these subgroups had a numeric advantage with UBX1325 over sham. This points to UBX1325 acting across all levels of severity for patients with diabetic macular edema and suggests that there's broad applicability of UBX1325 across the diabetic macular edema patient population. This pie graph is showing the rescues. These are patients at week 12 that had received an anti-VEGF injection as rescue, meeting very strict criteria for rescue. This is, that is either an increase of 70 microns or worsening of the macular edema on OCT or a visual acuity decline of 10 letters or more. You can see in blue for the UBX group, 69% of the patients required no rescue out to the 3-month time point. This is slightly better than what we see with sham, where 63% of the patients were able to avoid rescue to the 3-month time point. You can also see for the portion of the graphs where there was patients that needed either 1 rescue or 2 rescues. For each of these rescue categories, the UBX group was a smaller proportion of patients that needed this level of anti-VEGF rescue. Safety results are shown on this slide. Overall, UBX1325 had a favorable safety profile with no significant ocular tolerability issues. I'll draw your attention to the line that says treatment-related ocular treatment emergent adverse events for the study eye. There were six of these for the UBX group, and the majority of these were related to the injection procedure itself, events such as subconjunctival hemorrhage, irritation of the eye. These are things that we're used to that are associated with just the act of putting the needle in the eye. These were largely self-resolved and mild. Things that we would expect with the injection procedure. No serious adverse events or adverse events that were directly related to the drug. I'll draw your attention to the bottom line on this chart. These days in ophthalmology, we're very alert to any signs of drugs initiating ocular inflammation. For the finding of intraocular inflammation or endophthalmitis and other things, there were no events that were seen in the study. It's reassuring for the safety that there was no IOI that was elicited by UBX1325. I'll go through a few cases of patients in the study in terms of their OCT images. Just to remind you, shown here in the panel is a normal, perfect OCT. We have this nice smooth retina, fairly thin, and then this typical foveal architecture here with the depression. I'll show the first patient, and here we see a typical diabetic macular edema patient. The OCT is showing this thickening and distortion of the central macula. There is some flattening and loss of the foveal depression. We see those black spots that are intraretinal fluid cysts, and we even see an indication of some subretinal fluid here. After a single injection of UBX1325 at weeks 8 and 12, we see a reduction in that central subfield thickness. This is an 85-micron reduction in thickness. We see some restoration of that foveal architecture, and we see resolution of both the intraretinal cyst and the subretinal fluid. The next case is really one of the most severe cases. You can see here at baseline, this is a picture of chronic severe diabetic macular edema. The intraretinal fluid cysts have been so severe that they form this confluent sort of macro cyst. These are the patients that when we see them in clinic, we are not optimistic about response to treatment. With UBX1325 as a single injection in this patient, we can see that there's at 4 weeks some reduction in that macrocyst, and the macrocyst is resolved. It's gone by 8 weeks and 12 weeks. There's a dramatic decrease in the thickness of the retina, 250-micron improvement, and we see some restoration of the central foveal depression. This is a dramatic response. Certainly nothing that would be expected from natural course of the disease and an indication that we have a powerful UBX effect in this patient. In summary, a single injection of UBX1325 demonstrated evidence and support for this senolytic theory of treating patients with diabetic macular edema. There was an improvement in visual acuity in UBX1325 patients, treated patients, as well as in the diabetic macular edema and macular thickness on OCT. UBX1325 was well-tolerated with a favorable safety profile and particularly no evidence of intraocular inflammation that was elicited. There was an improvement in visual acuity that was durable after a single injection through 18 weeks. The BCVA gains were robust across a range of disease severity in terms of visual acuity and diabetic disease and OCT thickness. The UBX1325 showed maintenance of the retinal thickness and structure, as opposed to the sham-treated patients, which underwent the expected decline and worsening of the macular edema. This data is optimistic for the future clinical development of UBX1325 for diabetic macular edema and gives reason to hope that in the future we'll have a transformative therapy to add to our armamentarium for the treatment of diabetic macular edema with fewer number of injections to control this disease. With that, thanks very much. I'll turn it over to Jamie Dananberg. Thanks, Bob. I really appreciate you sharing those data with everyone. This is an exciting set of data that for us both confirms the senolytic hypothesis, but also recapitulates much of what we showed in our phase 1 study depicted on this slide, in two consecutive studies now showing the pharmacologic potential benefit of UBX1325. For the BEHOLD study, we have the 24-week readout coming by the end of the year, and we look forward to the full set of data that's coming from that study. We do have a long-term extension associated with that study and with patients having an option to remain in. So far, majority of patients who have reached their 24-week visit have opted into continuing in this study. We have the 48-week readout from that data next year. In addition, I'll remind everyone that we also have in parallel the ENVISION study ongoing, which is a study in AMD. That study we expect 16-week data by the end of the year. On this slide also shows the DME pivotal study. The data that Bob shared with you today moves us towards the direction of a pivotal study to start in the second half of next year. We will await the 24-week data before finalizing that study as well as regulatory interactions to help confirm the design. With that, I will turn it back to Anirvan. Thank you, Jamie, and thank you, Bob, for sharing the clinical data from the BEHOLD study. When we started this study, we were really going into uncharted territory to see whether a novel mechanism designed to target senescent cells in retinal tissue could provide durable benefit in retinovascular disease. We hoped that UBX1325 could be comparable and potentially superior to historic anti-VEGF. As you know, that is a high bar. As anti-VEGF therapies have been the standard of care for 15 years. As you've seen today, we find compelling evidence suggesting that UBX1325 could provide benefit to patients who are no longer optimally responding to anti-VEGF therapies. In this difficult to treat patient population, we find that a single dose of UBX1325 leads to a significant and sustained improvement in visual acuity and control of macular edema. This is an important validation of this senolytic therapeutic hypothesis and suggests that UBX1325 could be a valuable treatment option for patients with DME. We look forward to sharing the full 24-week data from this study in the months to come, as well as data from the ongoing study of UBX1325 in patients with neovascular AMD. Finally, I would like to thank the physicians and patients who participated in our studies and were helping us pioneer a new class of medicine. With that, we would be happy to take questions. Thank you, Anirvan. This begins the beginning of our Q&A session. I would like to remind the audience you may submit a question by using the Q&A function at the bottom of the webcast player or by emailing your questions to questions@lifesciadvisors.com. A reminder to our analysts, please raise your hand to indicate you would like to join the queue. Please hold for a brief moment while we pull for questions. Great. Our first question comes from Salim Syed at Mizuho. Salim, you may unmute your line. Got it. Great. Thanks for the color, guys, and congrats on the data. I guess I had one question on the, maybe a couple of questions on the rescue patients. Could you tell us at what, maybe I missed this, but what time point did the rescue patients get rescued, the 3 patients in the UBX1325 and also, I guess the 3 patients in the sham arm? Curious if you actually looked at the data without the rescue and if you were able to still have that 5-letter increase between the two arms. Just separately, curious to get your view, doctor, on the sham in this particular trial and why it didn't decline. Why was it actually maintained? It looks like there was actually quite a few letters increase at the beginning especially, and it was maintained at, you know, at 1 letter at 18 weeks. Hi, Salim. Let me start out, and then I'll hand it to Bob. You know, with regard to the rescue treatments, I just note that with the data we have right now, we do not have the data in yet with regard to the timing of the rescues. This is an important question that you asked, and so once we have the full data set at 24 weeks, we will have a better sense of when those timings happen and is there evidence that they were happening at different times in the two arms. I also note that this is still a relatively early time point with regard to what you're seeing. We're looking at kind of the data at 12 weeks, but of course, we're continuing to follow the patients. You can see their CST trajectory at least has continued to worsen in the sham arm between 12 and 18 weeks. One might expect that might lead to additional rescues as we go forward, at least in that arm. I'll hand it to Bob to address the se cond part of your question. Yeah. There's two parts to the remainder of the question. One is what are the results without anti-VEGF? I'll also get some support from Jamie Dananberg here. The analysis that we've showed have used this MMRM methodology as a way to look at the effects without anti-VEGF, okay? Once patients have received anti-VEGF, post anti-VEGF injection, the data are censored and not included in this analysis. It's an established and accepted way to look at longitudinal data and impute the results when there are missing data points. In fact, this is a methodology that's accepted and sometimes even encouraged by the FDA. The results that we showed are the models that show the effects without anti-VEGF. The last part of your question was about the sham group and the change in visual acuity. You're right, you know, there was within the first month or 8 weeks, there was a bump in both of the groups, but the sham group as well, a bump in the visual acuity, and then this then returned to decline to stay about the level of baseline. I think that initial bump is something that we've seen in some other early-stage trials, whether it's placebo effect or what, we don't know. Then for the stability of the vision in the sham group over this 3-month and 18-week period, it's kind of not unexpected. Diabetic macular edema is not a rapidly progressive disease as compared to something like macular degeneration. To me, it's not surprising that without treatment, over that time period, the patients with diabetic macular edema would remain relatively stable. It's actually one of the reasons that ethically, we could have a sham arm in this DME study. Great. Thank you. Yeah. Maybe, go ahead. Jamie, do you want to make a comment? Yeah. I was just going to add one or two simple things. The bump we saw in the sham was anticipated, Salim. As Bob pointed out, there are data in the literature, like the MEAD study that shows exactly that kind of magnitude of change in the sham group. It's partly why we wanted to make sure we brought in the 18-week data, because we didn't know ahead of time where that sham effect might ameliorate, which it does, and it's back to baseline by 12 weeks. That's a very important detail. Thanks, Jamie. Great. Thank you, guys. Congrats. Thank you, Salim. The next question comes from Yigal Nochomovitz at Citigroup. Hi. Great. Thanks for taking the question. I just had one high-level strategy question, then a few specifics on the data that was presented. On the strategy, Anirvan, maybe you can comment and also Dr. Bhisitkul. Obviously you've seen a nice early positive signal with one injection. You know, the obvious question I have, and I'm sure you've thought of and others are wondering as well, is for a future pivotal trial. You know, what would be the downside of doing a trial with two or maybe even three annual injections? It's still way better than what you would get with standard of care, so why not consider that? Yeah. Yigal, thanks for the question. You're absolutely right. You know, in many ways what we are seeing here is really the minimum treatment effect, the minimum that we can treat a patient with a single injection and looking at the effect. As you alluded to with anti-VEGF, the patients would typically get 3-5 monthly injections and then be on an every other month kind of regimen. As we consider the design of the pivotal study, this is high on our minds, and we expect to consider the possibility of exploring whether additional treatments might additionally benefit patients. I think we're already seeing a pretty impressive improvement in visual acuity and CST, but to your point, whether that is the maximum effect, we don't know yet, and we would be very keen on exploring it. You know, I'll note, we have previously commented that we had been targeting a treatment that could probably be given to patients once every 6 months. We're at 18 weeks now in striking distance from 24-week data. I would say that we have the first kinda line of sight that that kind of profile could be achieved. Then whether within that period one could achieve even a greater improvement, maybe with maybe a couple of initial injections would be something that is very is worth exploring. Okay. Great. Then just a few kinda rapid fire questions on the data. Can you just... I don't think you commented, but was the prior anti-VEGF use balanced between the arms? Yes. Okay, go ahead. Jamie, you comment on that. Yeah. Actually, Yigal, it was exactly balanced. The mean injection frequency in both groups was exactly 4.03 injections, so perfectly balanced. I might add, the study was balanced across almost every variable we looked at. That's a very important point. I'll also mention, Yigal, that we were able to look at you know, the prior 6-month treatment data, and it lines up exactly the way we would have expected. That's not part of the study data. You know, when I was giving the framework, I said it is expected that you know, beyond the 6 months, the patients were relatively stable. These patients who got about 4 injections the prior 6 months, on average, their CST was unchanged during that period. Their behavior coming into the study was exactly what we would expect for someone who's been on an anti-VEGF for 6 months or longer. Okay, great. Just for Dr. Bhisitkul, just two questions on the data. You mentioned in terms of the rescue that the percentages were a little bit lower for UBX1325. In terms of the absolute numbers, they were actually, I think, identical, 3. It's just could you just help us understand a little bit more, you know, why the total number of rescues was actually the same when you saw the obviously better results with the drug? Well, you know, the rescues are gonna be for the patients that are in the category of having, you know, the worst declines, okay? They don't, they can affect the overall mean, but they don't represent the mean change that we see here. Hey, Bob, just as a correction, Yigal, there were 4 rescues in the sham group and 3 in the UBX group for 2 or more rescues. With a single rescue, there were 12 in the sham and 10 in the UBX. Yeah. Sorry. It was not balanced. It was in favor of UBX. Okay. Sorry. I took the slides that fast. Yeah. I get it. It's okay. Sorry. Go ahead, Bob. Yeah, we were asking a question about your view on the results. The question of whether there should have been more separation in the number of rescues. I think it's just a factor of the rescues, really dealing with just the patients who are in the category of the more severe decline. Okay. Also, I just noticed on the CST profile for UBX1325, it sort of went up a little bit at eight weeks, and then it reversed back down. Is that just sort of, you know, natural variation, or is there anything more to read into that? Yeah, it might be. You know, it sort of, again, it tracked along with the sham group for that. Both groups had that initial bump in the OCT thickness. For the sham group, it went on to extend, to get worse and worse, whereas it resolved back to baseline. What the driver of that initial bump is, you know, it's not clear. I mean, maybe. Any of these individual patients, of course, it's not a straight line for any individual patient. It's bouncing. When I see a patient in clinic, they're gonna bounce within a range of 10 microns, 25 microns, almost as the natural course of the disease. Again, I'll point out that those changes that we see initially, I think it was about 20 microns. Most of us would think that 20 microns is sort of within the range of the noise, and it's when we get closer to 40 or 50 microns that we begin to say to ourselves, "Okay, I've got a significant worsening here. Yeah, Bob, I just wanted to add that, you know, when you think about the initial phase of all, right, after the patients get randomized. At that point, of course, we expect that our agent is in the system and eliminating senescent cells, but the retinal environment is still pretty toxic, right? You've taken their anti-VEGF off. There's probably fairly high levels of anti-VEGF, and some of those inflammatory factors are still there. They kind of need to resolve, and the benefit of the senolytic agent needs to kick in. It's not surprising to me that for the first few weeks you would have a bit more of a noisy trajectory. As you see, as you go forward, you know, 4, 8 weeks beyond, they settle down and start showing the treatment effect. In support of that, Yigal Nochomovitz, the shape of the curve from the phase 1 study was mirrored this shape very closely, suggesting that this kick-in effect between 8 and 12 weeks seems to be consistent. Got it. Thank you. Thanks for the questions, Yigal. The next question comes from Brandon Folkes at Cantor Fitzgerald. Brandon, you may unmute your line. Morning, everyone. Congratulations on the data, and thanks for taking my questions. Maybe just following on from one of the earlier questions. Just given the shape of the curves, how do you think about a loading dose regimen going forward? Right. And then secondly, just any commentary on the variability in patient responses in the groups, were they relatively uniform within a range or any outliers? Thank you. Hi, Brandon. Thanks for your question. You know, we're going to be thinking very carefully about the design of the next study once we have the full 24-week data set. We expect to share additional details of the design once we get to that point. I'll say that what is striking for us here is that we see that with a single dose of UBX1325, we're getting significant benefit in visual acuity. As you know, you've been following this story for a long time, that has been kind of the model because we believe that we could eliminate senescent cells and then see benefit. That is really super exciting for us. I think the question that you asked might pertain a little bit as to whether with regard to complete elimination of senescent cells for maximum benefit, could there be an initial period where patients who, let's say, get 2 doses four weeks apart or something like that might benefit more? Is there some period beyond which, let's say 6 months or beyond, where they get another dose that helps clear senescent cells that might have accumulated over a longer duration? These are things we'll be considering. Right now, I think it is important for us to establish, as we've shown, that with a single injection, we see an improved benefit that shows that we are engaging the mechanism the way we would want to. Did you have a second part to your question? I might have missed it. Yeah. Just if there are any outliers in the data. Yeah. I mean, so far, you know, you saw the curves that show the means and the standard errors, and I think that that's the level of analysis that we can share right now. We really, at this point, it is an interim analysis at 12 and 18 weeks. We'll have full single patient data when we get to the 24-week data set. I think at that point, we can further address these questions. One thing we did share today was, as we look across all the patients that Bob presented. If we look across the patients with a range of starting characteristics, the response was uniform across all of those baseline patients. There wasn't a particular group that disproportionately impacted the BCVA. It was representative across the entire population of patients. Great. Thanks very much, and congratulations on the day. Thank you, Brandon. Thank you. Thanks, Brandon. The next question comes from Andreas Argyrides from Wedbush. Andreas, you may unmute your line. Thanks. Good morning, everyone, and congrats on the impressive results here. I guess for- Uh-oh. Hmm. We lost him. What happened? Andreas, I think we lost you. Oh, there he is. I think he's back. Andreas, can you repeat your question, please? Oh, I'm sorry. Yeah. I've been having issues with this. I've been kicked off a bunch. Okay, no worries. The question, I guess, was based on the kick in effect that you saw from 12 to 18 weeks. How does that kind of form expectations for the 24 weeks based on the mechanism of action of 1325? For Dr. Bhisitkul, how do you look at the phase 1 results and that's patient population and then the results today and think of 1325 as a potential monotherapy? I will squeeze in another one here. How have these results, I guess, impacted expectations for wet AMD? Actually, now then I have one more. I'll follow up. Hi, Andreas. Yeah, let me start off, and then I'll hand it to Bob to address the second part of the question. The expectation you'll recall of a senolytic agent is it's essentially a sequence of events that happens as we remodel and restructure the retina to a better state, primarily through an effect on the vasculature of the eye. Our expectation in the preclinical data we have is that we should achieve senolysis fairly rapidly after the drug has been introduced in the eye. You know, this is a small molecule that resides in the eye for only about a week or two. You know, for us, it's particularly impressive that after that very brief presence in the retina, you're getting these long-lasting effects, which is predicted based on the mechanism. Which is once you remove the senescent cells, you then trigger a process of healing that would first involve, you know, restoration of barrier function as the senescent cells are removed, enabling healthy cells forming tight junctions, beginning to improve perfusion in the retina. In preclinical experiments, we've also seen very evident, nice evidence of remodeling of the vascular structure to get healthy capillary beds. That should then have downstream effects on retinal function and improved health. Ideally, we are also eliminating kind of the toxic environment, the inflammatory environment that was being created by the senescent cells, and so thereby essentially resetting the retina. Now, what is interesting is that even out to 18 weeks, between 12 and 18, we continue to see improvement, right? There's a question like, you know, when does the effect plateau? We haven't gotten to that plateau yet with the data we have. We'll see whether when we get to 24, whether it kind of stays around 18 or whether it continues to improve. I think that'll give us a sense of, you know, over what time course does the retina get to its kind of ideal state or restored state. But the fact that we expect a certain amount of remodeling the vasculature to happen and then lead to benefit is consistent with the trajectories that we are seeing. Bob, I'll hand it to you to answer the second part of Andreas's question. Yeah, Andreas, the second part, I think, was about the ongoing wet AMD study and what we can expect from DME and does it give us any indication of what we'll be seeing in AMD? You know, of course, they're very different diseases. There's a different treatment protocol in for AMD than there is for DME. In the ENVISION study, there's going to be two injections at 10 micrograms, one at baseline and one at four weeks, for a higher dose of UBX1325 in AMD, which is a more aggressive and rapidly progressing disease. You know, historically, drugs that have had a benefit for DME have also shown good benefit for macular degeneration. That's not, you know, straightforward to extrapolate to the case here. You know, as you mentioned with phase 1, we've seen some extension and support of the phase 1 data here in the larger phase 2 study with many more patients. Maybe we can hope that we'll see a similar extension for what we saw in wet AMD in the phase 1 within the phase 2. Again, I think in the ENVISION study, we have a more robust treatment protocol in those patients. Bob, there's also a question about monotherapy. Yeah, I just wanted to come back to Andreas, ask the use of UBX as a monotherapy. I think that was one. I mean, the nice thing about this protocol is it is given as a monotherapy and then followed out to six months. It's gonna be very interesting there. I don't think it. I mean, I can envision that this would be a pretty typical clinical pattern that we would use for our patients in the real world, you know, where you might start with this single treatment. Of course, anti-VEGF is always gonna be available to the patients, and we'll use it where it's needed. I think this start with UBX1325 and then follow it with rescue as needed might be one approach that we take. You know, I think it's worth exploring in the future for the clinical development what happens when you combine, when you use UBX1325 with an anti-VEGF protocol, particularly in DME and in AMD as well. It's worth exploring, but it's not something that we're seeing that we can comment on from the results of these studies. Does that answer your question, Andreas? Yeah. Yeah, very much. Thank you. Congrats again on the impressive data. Thanks, Andreas. Thanks, Andreas. The last question will come from Elemer Piros at Roth. Elemer, you can unmute now. Yes, good morning. Thank you so much. I just wanted to maybe one last time to clarify how the rescue injected patients were treated for the analysis. Is it correct if I may understand it correctly, that the data from those patients is actually included only prior to the rescue injection? Or has that been as an alternative, or are they completely excluded from the analysis if they- No. Jamie, why don't I pass this one. Anirvan Ghosh. Yeah, yeah. I'm gonna, Bob, let me take that. Elemer, so the way the analysis is carried out is an MMRM analysis, which is a well-established methodology, a preferred methodology for datasets like these, repeated measures datasets. Just a point of clarification, which is that it is designed, it's an analysis that is designed so that you can see or understand the full treatment effect of the agent that is being considered. In other studies, for example, it might be used to account for, you know, some level of missing data, which datasets might have because a patient missed a visit or something like that, and you don't want to confound that analysis. In our case, it allows us to effectively fully evaluate the UBX1325 treatment effect. With regard to the data that are included, you're right, so that all of the data points that are pre-rescue are part of the overall analysis. The data points from those subjects who did get rescued and hence have a confounded effect of anti-VEGF, that anti-VEGF effect is removed. That takes care of that. That's the way the analysis is designed. Andreas, is the patients are not removed from the study? It's not an LOCF model. There's an imputation for the data post-rescue from a you know more sophisticated statistical model. The totality of the patients are still included at those subsequent data points in the statistical analysis. Have you done the analysis when you kept all the data and looked at all the patients with and without rescue at the 12 and 18-week time point? Yeah. Let me comment on it. I think there's a statement that Bob made about that. If you were to look at data that includes the VEGF treatment, and obviously at that point then you're looking at a composite effect, that the effect that you see is you see that in the sham arm you see evidence of a treatment benefit with the rescue. We do not see evidence of additional treatment benefit of anti-VEGF on the UBX1325 arm. That indicates that UBX1325 is providing a visual acuity benefit to patients on top of which anti-VEGF is not adding. It's also consistent, kind of the way we think about senescent cells acting pretty upstream in the process. I think all of those observations are consistent with the way we think about senescent cells and disease progression. Thank you. Thank you very much for the response. Thanks, Elemer. This concludes the Q&A session for today. I will now hand it back to Anirvan for concluding remarks. Thank you, Sarah. Thanks everyone again for joining the call and the questions. I'll just make a couple of remarks. You know, for us, this is really a pretty remarkable moment. As you know, we've been talking about the expectations from this study, including benchmark data, for months now. We knew that anti-VEGF treated patients who have been on anti-VEGF for more than six months are not expected to gain vision beyond that with continued anti-VEGF treatment. It's almost as though there is a certain barrier to vision improvement. I would say that many of the KOLs, investigators in the field thought it would be very, very challenging and unlikely that you could get vision improvement beyond what patients have gotten with six months or more of anti-VEGF treatment, simply because that has not been seen. I think that the data we have today really provides compelling evidence that is not necessarily the maximum benefit that a patient can achieve. That a mechanism, an orthogonal mechanism and a novel mechanism of action can change the trajectory of retinal health in a way so that you can get benefit beyond what historic anti-VEGF would have suggested. For that, for us, it's a remarkable result. I think it's a exciting result for the retina community, for whom there have been very limited options beyond what you could do, with anti-VEGFs. Essentially all you could do is give them more anti-VEGF, which is what is happening in these patients. Incredibly heavy treatment burden of needing a treatment, in this case, every 6 weeks or so. We are really pleased with this initial data set we have. Of course, we're gonna be looking forward to the 24-week data from the DME study and to the 48-week data in the months to come. We are excited about the way the neovascular AMD study is progressing and look forward to sharing data from that AMD study as well, in the coming months. Finally, once again, I'll iterate that although the you know, the study is sponsored by us, it's been core to Unity, this is truly a community effort. The physicians on the study, the sites, the patients, they are all critical components. Over the last few months, Jamie and I and the team, we've had a chance to go to many of the sites, meet with them. We've repeatedly talked to them at scientific conferences to influence our design. Numerous investigators who are very familiar with the field helped us think through what is the right way to explore and reveal a potential treatment benefit. I just want to close by thanking everybody who got us here, and I look forward to future interactions.