Good morning, and welcome to the Unity Biotechnology KOL Webinar, an update to the lead program, UBX1325. At this time, all attendees are in a listen-only mode. A question-and-answer session will follow the formal presentations. If you'd like to submit a question, you may do so by using the Q&A text box at the bottom of the webcast player or by emailing your questions to questions@lifesciadvisors.com. As a reminder, this call is being recorded, and a replay will be made available on the Unity Biotechnology website following the conclusion of the event. I'd now like to turn the call over to Lynne Sullivan, CFO and Head of Corporate Development at Unity Biotechnology. Please go ahead, Lynne. Good morning. Thank you for joining Unity Biotechnology's conference call this morning to discuss the 24-week data results from our phase I single ascending dose study of UBX1325. We will also be sharing 12-week data from an additional cohort of 7 AMD patients dosed to 10 mcg. With us on today's call is Dr. Robert Bhisitkul, Professor of Ophthalmology and Director of the Retina Fellowship at the University of California, San Francisco, and Dr. Arshad Khanani, Managing Partner and Director of Clinical Research at Sierra Eye Associates. From Unity, we have Anirvan Ghosh, the CEO of Unity Biotechnology, Jamie Dananberg, the CMO of Unity Biotechnology, myself, Lynne Sullivan, the CFO. 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 do not assume any obligation or intent to update them except as required by law. With that, I'll turn the call over to Anirvan. Thank you, Lynn, and thanks to everyone joining us on the call today. We're pleased with the progress we're seeing in our phase I study of UBX1325 in advanced patients with DME and AMD. I'm going to start with a brief background on Unity and then hand over the call to Dr. Arshad Khanani, who will provide a background on the therapeutic landscape. Then that will be followed by Bob Bhisitkul, who will share the data with you. If you go forward to the next slide, at Unity, we are focused on developing medicines to slow, halt, or reverse diseases of aging. Our primary focus is in ophthalmology and neurology, and today we'll be sharing data from our ophthalmology program. The next slide provides an overview of some of the major milestones and the data we'll be sharing with you today. Importantly, our lead program is UBX1325, which is currently in two studies. We have a phase I single ascending dose study that's ongoing, where we'll be sharing 24-week data with you today. We'll also be sharing data from an expansion cohort of AMD patients that have now been followed through 12 weeks. We have a phase II-A study in DME that has started enrolling. We expect to have 12-week data from that study in the first half of next year, and we intend to start a phase II study in AMD early next year, and we expect to have data from that study in the second half of 2022. If you go forward to the next slide, we see a snapshot of our pipeline. As I mentioned, UBX1325 is our lead program that is currently in a phase II study as well as in a phase I study. Behind that, we have UBX1967, which is also a BCL-xL inhibitor that is in GLP tox studies. UBX2050 is a TIE2 agonistic antibody. Behind that, we're working on a bispecific TIE2 VEGF antibody that we're quite excited about. In neurology, the key programs are Klotho, which is a pro-cognitive biologic, and we're working on a senolytic program in the nervous system as well. The next slide provides an overview of the senolytic approach. Going from left to right, you see a representation of a tissue as it ages, and you can see an accumulation of blue cells as you go into the second and third panel. Those cells represent senescent cells. We know that as our body ages across tissues, there's an accumulation of cells that under stressed conditions, including DNA damage, will stop dividing, but they remain metabolically active. These cells can secrete factors that can be damaging to the local microenvironment, and we believe that can lead to disease progression. Our therapeutic approach is to develop molecules that can selectively eliminate senescent cells while leaving the neighboring healthy cells unaffected. If you do that, we expect that we will remove the root cause of disease progression and thereby allow the tissue to restore itself and ideally improve patient outcomes. If you go to the next slide, I want to briefly describe where UBX1325 acts in the cascade of eye disease, in this case, shown for diabetic eye disease. In diabetic disease, in response to cellular stress, you get an accumulation of senescent cells in the retinal vasculature. Those cells, in turn, can release a number of inflammatory factors shown right below. These factors includes factors such as VEGF and Ang-2 that we know are involved in the disease pathophysiology. Eventually, that can lead to disease progression and loss of vision. UBX1325 is a BCL-xL inhibitor that is designed to selectively eliminate senescent cells and thereby prevent or reduce the inflammatory output from those cells. In addition, we know that UBX1325 can have a more acute effect on vascular leak and thereby reduce fluid accumulation. By these two mechanisms, we believe that UBX1325 could lead to an improvement in the pathophysiology of disease and improvement in vision. The next slide provides an overview of our aspiration for UBX1325. As you know, the standard of care in this field are anti-VEGF treatments. Patients on anti-VEGF will typically have a loading dose of anywhere from 2-5 injections, depending on the indication, and then have multiple doses during their first year of treatment to manage the disease. That leads to a significant patient burden, and Dr. Arshad Khanani will share with you briefly. We hope that with UBX1325, by eliminating senescent cells, we could have a rapid effect on improvement in vision and with greater durability than we currently see with the standard of care. Because it is a novel pharmacology, we believe that it could work as a monotherapy or potentially in combination with anti-VEGF agents. We have previously shared that UBX1325 in preclinical models is also able to improve vascular flow and lead to healthy blood vessel growth into ischemic areas of the eye, and that could be a differentiation compared to current anti-VEGF treatments. For all of these reasons, we believe that UBX1325 could be an important future medicine in the treatment of DME and AMD and could have the possibility of truly modifying the course of disease. With that, I'm going to hand the call over to Dr. Arshad Khanani, who will go over the current therapeutic landscape. Good morning, everyone. Thanks, Anirvan. Over the next few minutes, I'll be discussing the retinal diseases therapeutic landscape, as well as unmet needs in our patients with DME and neovascular AMD. I'm sure most of you have seen the slides I'm going to show you, but I think it's important to keep in mind the physician perspective as well as patient perspective when we are looking at new treatments in the pipeline. Next slide, please. Here you can see in patients with DME, with the current approved agents, aflibercept as well as ranibizumab and off-label agent bevacizumab, you can see that our patients require frequent injections to really maximize the visual acuity outcomes. Here you can see the results from the Protocol T study, where you can see, on average, irregardless of the agent you're using, we are giving about 9-10 injections in the first year to really get the visual acuity outcomes we would like to see. Obviously, in clinical trials, patients are much more compliant because, for example, if they miss an appointment, my coordinators will call them multiple times. We'll send them certified letters. The outcomes we are seeing obviously are much better than what we see in our clinic on a daily basis. Here in the next slide, what you will see is the work done to look at patient outcomes. Let's wait for the slide. Okay, great. Here you can see Tom Ciulla published this recently, and you can see the high number of anti-VEGF injections that are needed for better vision outcomes in DME. If you look at the y-axis, you can actually see the mean visual acuity change in letters. Of course, these are ETDRS visual acuity. You can see that even with 10, 11, 12 or 13 injections, the number of letters that we are gaining are close to 7-8 letters. If you have minimal injection, let's say 2 or 3, you're not gaining much vision. This really highlights the problem we have as physicians in our clinic, where we need to bring these patients for frequent injections to maximize the visual acuity and essentially needing a high number of injections in the first year to get 7-8 letters of vision. Next slide, please. This is a very interesting analysis from Protocol I. What this really emphasized that there's need for novel therapeutic approaches to improve clinical outcomes as well as to improve suboptimal patient response. Here you can see by week 12 in this study, only 60% or so patients had 5-letter gain or higher, and then 37% had 10-letter gains or higher. You can see that majority of our patients are not getting over 10 letters of gains. When you look at the visual acuity improvements, you can see that after the initial loading doses or initial few treatments, patients are actually staying in the swim lane. Their visual acuity response is really shown by week 12, and then after that they're not improving much. What that highlights is the need for novel mechanism of actions, novel treatments to really seeing those patients gain more vision. We all know that from pivotal trials, the RISE and RIDE, VIVID and VISTA, only 30%-40% of our patients are gaining 15 letters of vision, which is very clinically significant. There is majority of patients that are not gaining those vision even in clinical trials. Of course, again, highlighting the need for novel mechanism of actions and also durable agents to help our patients in clinic. Next slide. Here you can see, looking at neovascular AMD, this is our PAT Survey that ASRS does every year. Physicians still identify treatment and monitoring burden as a key unmet need, despite some flexible dosing. You can see reducing treatment burden is the first, most important thing as physician. I'll tell you know, I saw almost 90 patients every day last week, and many of my patients waited a long time. And really, as the population is getting older, we really need treatments that are more durable so that patients are not coming into our clinic frequently because the system cannot handle it. That's why reducing treatment burden from a physician perspective as well as a patient perspective is super important. You look at longer-acting or sustained delivery. That's another big unmet need where you have agents that can last longer than current available agents. Most of the agents approved at this point, obviously go up to 8-12 weeks maximum, in a subset of patients, not in all patients. Then of course, new treatment or mechanism of action. Looking at new actions to modify these diseases is important. Reducing treatment burden, long-term or sustained delivery, and then using new mechanism of actions. Those are the key things I want you to keep in mind as you see data from Dr. Robert Bhisitkul later. Next slide, please. Here, from a patient perspective, as I was saying, and this is unmet need both in DME and neovascular AMD. The frequent treatment and monitoring requirements place a heavy burden on patients. You can see on the left reasons patients feel that frequent monitoring is unfeasible. This is high treatment burden coming in every month or every other month. Transportation issues, because a lot of these patients need to bring a driver with them after getting an injection, they cannot drive. A lot of these patients are actually getting bilateral injections, so obviously they cannot drive after that. Time-consuming, as I said, when I'm seeing 90 patients or so in my clinic, patients are waiting anywhere from 2-4 hours to get their treatment. Reasons for patients' discontinuation of follow-up. You can see long distance travel times, dissatisfaction with benefits of treatment, because as you saw in Protocol I, you can see there's a plateau on visual acuity, and most of these patients are not seeing any improvement after the first 3 - 6 injections. The burden of follow-up visits, as I mentioned, coming to my clinic or any clinic and waiting in there. Next slide, please. I hope just looking at the last few slides I presented, you realize that there's actually urgent need for innovation in our field. Future treatments for DME as well as neovascular AMD patients should reduce the frequent injection and treatment monitoring requirements that place a heavy burden on patients. Target novel pathways to address the suboptimal responders and improve clinical outcomes with the potential for disease modification. Of course, durability is a big issue. Enhance long-term efficacy and durability. Keeping these things in mind, I'll pass it to Dr. Bob Bhisitkul to present the latest data for you. Thanks much, Arshad. From that background, I will give an overview of the 24-week data in the phase I study with UBX1325 in these patients with diabetic macular edema and neovascular AMD. Keeping in mind that these are advanced patients who are poor responders or incomplete responders to anti-VEGF therapy. On the first slide, we see the single ascending dose design of this study. As I pointed out, the major eligibility criteria were that the patients with diabetic macular edema had to have center involved DME, central subfield thickness greater than 350 microns. For the neovascular AMD subjects, they had to have active choroidal neovascularization. This is evidenced on both the FA and the OCT that there's leakage and fluid accumulation. Here, the visual acuity criteria were that the study eye had to have 20/80 or better, and then after that it was 20/80 or worse, and after that it was 20/40 or worse. One other thing to keep in mind is for the patients in the ascending dose study, it required that they had had previous anti-VEGF therapy, and the physician assessed that they were not gaining benefit from the anti-VEGF therapy. Another thing to point out is that the design of the study required a 90-day washout. Three months prior to entry into the single ascending dose study, the patients were required to be kept off of any anti-VEGF injections prior to the subsequent 24-week study. We can go to the next slide. This is just showing us a schema showing the design of the study and showing the four dose cohorts starting at 0.5 mcg per eye and going up to 10 mcg per eye, with three subjects in each dose cohort. You can see here we're showing the DME patients in blue. In each cohort, there were two DME patients and one neovascular AMD patient. The highest dose cohort also then gathered a group of 7 neovascular AMD patients, and those patients are the ones that are still underway, whereas the previous patients have all reached the final 24-week endpoint. We can go to the next slide. First and foremost with any phase I study is, of course, safety. Looking at all of the events and reports from the patients that have gone through the phase I study, UBX1325, given as a single intravitreal injection, was found to be safe and well-tolerated. There were no dose-limiting toxicities or intraocular inflammation that was seen. There were no SAEs reported. The overall profile of safety, both for the ocular safety of UBX1325, is that there were no contraindications to proceeding with later stage clinical development. Moving on to some of the other endpoints. Looking at efficacy, improvement in vision was seen in both groups. There was approximately a 10-letter mean improvement across, on average across the patients with DME in the higher dose groups. The majority of the macular degeneration patients maintained or improved their visual acuity through the 3-month study. We also used as a secondary endpoint the OCT findings and the anatomic changes. There was a central subfield thickness decrease from the baseline entry into the phase I study in most of the AMD and DME patients, with either stable fluid or improvement. The majority of these patients did not require anti-VEGF rescue during the course of the study. In some patients, a complete resolution of the fluid that was seen on OCT as well. As we go through, I'll be able to show a few demonstration cases. We can go to the next slide. We'll show this in two groups. First, we'll show the DME patients, and then we'll show the AMD patients. This is the phase I first-in-human study. Let's start with the DME patients. We'll take the next slide. This is showing the patients with DME, showing their mean change in vision from baseline. We can see overall, across all dose groups, the line is shown in blue. We can show the two highest dose groups, the 5 mcg and 10 mcg, those patients are shown in green. Just as a comparator, we obtained the visual acuity in the fellow eye. It was a non-study eye, and that's shown in the gray line. It's interesting to see that after the single dose of UBX1325, there was an improvement that was seen in the visual acuity on average, and that this improvement was seen at 12 weeks and then even extended in a fairly consistent and maintained manner out to 24 weeks for the endpoint. A sustained and stable improvement in vision on average after a single UBX1325 injection over the course of this three-month study. We can go to the next slide. I'm sorry, over the course of the six-month study. This is showing the patients with DME through 24 weeks in the dose escalation group. This is just showing each of the doses broken out, and we can see again the improvement in vision that was seen at 12 weeks is sustained and carried out over 24 weeks in a fairly stable therapeutic plateau again. You know, it brings to my mind at least the mechanism that Anirvan has talked about for this senolytic therapy, something that's modifying the disease and modifying the cell populations in these diseases. It's at least consistent with what we're seeing here with a 6-month improvement and stability in the vision. Again, as a retina clinician, this is in the face of patients that not only are they by protocol taken off of the anti-VEGF therapy for the 6-month course of this study. Prior to that, they had had three months of washout from anti-VEGF. For the majority of these patients, this represents six months with no anti-VEGF therapy. I think most retina practitioners would agree that in that setting, for DME and for AMD, if you had withholding of their patient's anti-VEGF therapy for that extended period of time, we are expecting a decline in the majority of these patients. Just as a cross-study comparison, really just as a sort of marker. The circles that are shown in red there with the crosses, that's data taken from the aflibercept study, the VIEW study in DME patients, and put in there just for context for the type of vision gains we're seeing in these, in these admittedly much smaller numbers of patients. We can go to the next slide. Here, we're concentrating just on the patients in the two higher dose cohorts with DME through 24 weeks. Again, with the change in vision, we can see that with the change in vision for baseline, we can see at least a suggestion of a dose-dependent effect across these patients out to 24 weeks. Again, in the three of the four patients, we see that that stable vision gain that's seen at 12 weeks is maintained out to 24 weeks. We can see the next slide. A significant proportion of the patients with this advanced DME were found to have vision gains after a single injection. The chart on the left here is just showing the patients who gained 10 letters or more and the patients who gained five letters or more. Here we're seeing at week 12 and even out to week 24, 62% of the patients gained at least five letters and 37% gained at least 10 letters. These are favorable outcomes overall, and they can be compared to previous studies, where we've seen quite similar results in DME patients and in this case, naive DME patients, treatment-naive DME patients, where there are similar numbers that are seen for these two thresholds of vision gain. We can go to the next slide. In any phase I study, there's a rescue protocol with withholding the anti-VEGF. There are criteria in place to retreat the patients with anti-VEGF if they meet these criteria. Another thing to indicate the stability is that out to 24 weeks, 62% of the patients did not meet the criteria to require an anti-VEGF injection. This is over the six-month period of the study. The majority of the patients did not meet criteria to require rescue. Another sign of stability from this single injection in the setting of withholding anti-VEGF for six months during the study. We can go to the next slide. This is looking at the OCT changes. Here, we're looking at the central subfield thickness, and we can see in the high-dose patients, the two high-dose groups with patients with diabetic macular edema, there was at least an initial improvement. That is a reduction in the central subfield thickness after a single dose of UBX1325, and the patients had at least stable OCT out to 24 weeks after this single dose. Again, this is in the setting of withholding anti-VEGF over this period for six months in the three-month washout period. We can go to the next slide. Let's switch and talk now about the neovascular AMD patients. We can go to the next slide. Here, we're looking at the mean gain in vision. Now, there's a smaller number of the AMD patients in the single ascending dose. And then in the patients that are in the AMD cohort at the highest dose, not all of those patients have finished the 24-week endpoint. We're just showing the 12-week endpoint here. Again, after a single injection of UBX1325, the overall mean, there was an improvement in the visual acuity change from baseline, and this is sustained at least to some extent out to the 12-week endpoint in these patients with neovascular AMD. We'll take the next slide. We can look at this for each dose group here. We can see that again, there's this in two of the four dose groups, there is improvement in the visual acuity that's at 12 weeks, and this is sustained in a fairly stable fashion out to 24 weeks. We'll point out that there's one patient here, and we might refer to this patient later on, patient 0015, that had a significant decline in vision at week eight and despite rescue never recovered vision. The group at Unity, along with the KOLs and advisors, spent a lot of time looking at this patient. It was determined that this patient was thought to have not macular degeneration, but polypoidal choroidal vasculopathy, and probably didn't meet the initial criteria to enter into this study. These types of patients will certainly be excluded from any further studies. Some of the analyses that we'll go through when we look at the AMD patients will be exclusive of this patient that's thought to have polypoidal choroidal vasculopathy, PCV. We can go to the next slide. This is looking at the OCT again at the central subfield thickness, and this is the patients with wet AMD. Here we can see some improvement in the OCT, that is reduction in the central subfield thickness. This is carried out again after a single treatment out to 24 weeks in these patients. Again, an indication of a sustained anatomic improvement in these patients after a single injection of UBX1325. Next slide, please. This is looking at the patient's mean change in baseline of central subfield thickness and showing, again, the reduction in the central subfield thickness out to 12 weeks. I'll point out and we can discuss this further if necessary. This is using a last observation carried forward method for patients that receive any anti-VEGF rescues. We can go to the next slide. I'll close by talking about a couple of cases, and as retina doctors, we like to see these cases. It makes it sort of concretizes what we're seeing in these graphs. We can show the first patient who has diabetic macular edema. We'll take the next slide. We'll concentrate looking at the OCTs, which for us are useful to see the effect. This is a patient in the 5-milligram dose group with diabetic macular edema. We can see from that image at day zero or baseline, we have severe, I mean, very severe diabetic macular edema with these large cysts and these chronic-appearing diffuse CME. We can see at week four that after a single injection of UBX1325, there's an indication of improvement there. There's not resolution of the DME, but in this very severe case, we see qualitative improvement and some reduction in the thickness on the OCT. We can see that this is carried out through week 12 and out to 24 as well, with a reduction in the size of that large chronic cyst. In this patient, this is associated with a vision gain as well from baseline that we can see on the graphs below. We can go to the next case. This is a patient with neovascular AMD, and we can see in the day zero baseline study, we see that black fluid underneath the retina. That's the subretinal fluid that's sort of a classic hallmark of neovascular AMD. By week four, there's this hint that there's some reduction in this subretinal fluid after injection of UBX1325. By week 12, and carried out to week 24, there's complete resolution of that subretinal fluid, which is certainly not the natural course of wet macular degeneration. Again, in the setting of withholding anti-VEGF therapy in this patient for 24 weeks, it's indicative of resolution of the subretinal fluid after a single injection of UBX1325. In the graphs below, you can see that this is also associated with the vision gain in this patient. We can take the next slide. This is showing another AMD patient. Here, we can see it's a little harder to pick out, but you can see those little black bubbles underneath the retina on the right side of that whitish mound. That mound is what we call the SHRM. It's probably the subretinal, it's the choroidal neovascularization along with some subretinal fibrosis. We can see by week 12, those little black bubbles have disappeared completely, along with some very subtle fluid along the left slope of that fibrotic tissue as well, and that this resolution of the subretinal fluid is sustained out to 24 weeks. Again, associated with this patient showed some improvement in vision. We can go to the next slide. Here, I will turn it over to Jamie for the further discussion. Thanks, Bob. Greetings, everyone. I really appreciate Bob sharing the data that we have. We're very excited by the kind of changes that we're seeing, especially after a single injection of UBX1325. In addition, we're also noticing an important distinction between DME and AMD. We thought it was useful to remind ourselves that while, you know, in the era of anti-VEGFs, where there's a tool for all, we know that these are distinct diseases. While we believe there is a broad mechanistic role that senescence plays in both diseases, the fact is that where we see activity and how we see that displayed and what UBX1325 needs to do will need further optimization because of those two diseases. As you see on the left, the layering of the very healthy retina. We know that in DME, the main affected cell is the retinal vascular endothelial cells, shown in kind of bluish at the top of that middle panel in the dark blue. The factors that are produced by the senescent cells surrounding immunocompetent cells that are drawn to the tissue leads to vascular insufficiency and inflammation in that retinal layer. In contrast, in AMD, we know that the cells that are implicated as senescent in that disease are principally in choroidal vasculature and retinal pigment epithelial cells. You could see the adjacent photoreceptors with the release of inflammatory and other active factors from the senescent cells, leading to additional changes in function of the retina in a different location. What this all suggests to us is that we need to optimize the treatment regimen uniquely for DME patients and for AMD patients. That's something that we fully expected from day one, and we look forward to taking that work forward. If we go to the next slide. This is not an example. This is the phase II ongoing DME study, which is enrolling and has been enrolling since mid-year in patients with DME. Now we're looking at a population of patients who are somewhat less advanced than what we saw in the phase I study. These are patients who are currently on anti-VEGFs but are still not fully responding to that agent. They are still having residual fluid of at least 300 microns of central subfield thickness, and they still will have poorer visual acuity running at 20/40 or worse. These patients have been randomized to either receive a single injection of UBX1325 or randomized to receive sham injection and then they're followed, and we expect to have the 12-week efficacy data from this study as well as the 24-week efficacy data subsequently. The kind of endpoints that we're evaluating is, of course, ongoing safety and BCVA changes in CST, but also importantly, the proportion of patients who do not need rescue with anti-VEGF. You saw from the phase I study that we're achieving high levels of patients not needing rescue from anti-VEGF for as much as six months. That would be quite a transformational outcome from a study like this. Of course, we're looking at other endpoints that are even more unique to an agent like UBX1325 related to its mechanism of action to restore more vascular homeostasis to the retina. Other measures we're looking at include incidence of capillary non-perfusion and flow in the retinal vasculature using in this case wide-field fluorescein angiography. With that, I will turn this over to Anirvan. Thanks, Jamie. If you can move forward to the next slide. I just want to provide an overview of where our studies are. Today we shared data from the phase I study that the first single ascending dose study is now complete at 24 weeks. I think hopefully you share our enthusiasm for the data we're seeing. It's pretty remarkable to see patients going out to six months after a single injection of UBX1325. The expansion cohort of AMD data, we've shared 12-week data, but those patients continue to be followed through 24 weeks, and we'll update you once we have that full data set. Jamie mentioned that we have initiated the phase II study in DME, and that is a sham-controlled study, and we expect to have 12-week data in the first half of next year and 24-week data in the second half of next year. We just decided to initiate an AMD phase II study, which will start in the first half of next year. We hope to deliver 12-week safety and efficacy data in the second half. You know, if you go to the next slide, I just want to kind of refer back to some of the elements we're looking for in UBX1325 and where we stand. Arshad started out by reminding you that there's heavy treatment burden and suboptimal response, and many of the patients are currently on anti-VEGFs, and many of them requiring many injections to be able to achieve maximal benefit. The early data we see so far is very encouraging. After single injection in many of the DME patients, we see sustained response up to six months, which really I think is rare and possibly unprecedented in terms of another agent that can give that kind of durability. In AMD patients, we shared the 12-week data and some 24-week data. We'll continue to follow those patients. Jamie pointed out the difference in the pathophysiology in the two diseases which might inform the final dosing regimen. In the phase II DME study, we feel quite comfortable with the design we have right now, which is a single treatment followed to 12 and 24 weeks. In AMD, based on the trajectory of vision, we're considering the possibility of having a second dose in those patients that might maximize the benefit in those AMD patients. As Bob pointed out, even for those AMD patients, they were not responding to anti-VEGFs previously. To see some gain in those advanced patients is very encouraging and as we go to more moderate patients, we might see greater efficacy. Overall, I think for us it's really quite rewarding to see that the profile of UBX1325 as it is evolving is quite consistent with the mechanism of action and what we had seen in our preclinical models. We look forward to sharing data from these ongoing studies and future studies as we move forward. I'd like to thank Arshad and Bob for joining us today on the call. Thanks for providing the background about the current therapeutic landscape and for your assessment of the current data. The feedback that we've gotten from these experts as well as many other KOLs in the field has been hugely important for us in designing the study as we move forward. Also, Jamie, thanks for sharing the phase II design. With that, I'll hand the call back to Tara so that we can go to Q&A. Thank you. Thank you, Anirvan. At this time, we'll be conducting our question and answer session. If you would 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. Please hold while we pull for questions. Our first question comes from Brandon Folkes at Cantor Fitzgerald. Brandon, you may now unmute your line. Hi. Thanks for taking my question, and congratulations on the data, and thank you very much, Anirvan and team, for this data. I guess just one from me, Anirvan, following on sort of from what you said there. You know, as we see this data evolve quite nicely, and given that we now have data through the 24 weeks, do you see evidence of disease modification? Now, obviously, yeah, there's a lot of limitations on that question I'm asking, but, you know, just maybe versus sort of your preclinical models, how do you think. You know, any elaboration on that disease modification effort, granted, you know, small patient population and single dose, but just how you would expect it to compare versus expectations at this stage. Yeah. Thanks, Brandon. Just as a reminder about the mechanism of action here and how we can assess disease modification, I think an important thing to remember is that these drugs are in the eye for a very short period of time, right? UBX1325 is a small molecule BCL-xL inhibitor that's being given intravitreally. Based on all the data we have in preclinical models and our modeling of human PK, we expect the drug to be off the eye within just a few days, right? It is exerting its effect on eliminating senescent cells within the first few days. That's what we see in animal models. Everything that we see beyond that is a consequence that is not PK-driven. It is important because I think part of what causes one to require a lot of anti-VEGF treatments is you're kind of dependent on sequestering VEGF during the entire period of treatment. As the anti-VEGF goes away from the eye, then, and the VEGF comes back, you have to then dose again. In this case, what we are seeing is really prolonged PD well after the PK period, which would be one signal, I would say, of potential disease modification. Also importantly, if you remember some of the images that Bob showed, that you see kind of this longer term resolution of fluid. You know, you see, you follow them out to eight weeks, 12 weeks, 24 weeks, and you're seeing the retina remodel itself to a healthier state well after the drug is gone, right? For us, that is consistent with the idea that you are affecting a fundamental biology very early in the process of treatment, that is having a lasting effect, and that could be consistent with that. I don't know, Bob, if you want to elaborate on the kinds of things that one would look for that might indicate that this could have a disease-modifying effect. Yeah. I mean, Brandon's question, we have a, you know, a scientific mechanism here that's very intriguing and very novel. You're actually clearing out the sick cells, and you're remodeling the cell population. So, you know, it's a fascinating mechanism. How do you measure or monitor that? You know, it's not easy, especially in a living human being, you know, where we can't take their eyes out and do histology on it. So as Anirvan pointed out, you know, the first thing is just the phenomenological effect, that here we have a sustained effect from a single injection in patients who should be going downhill. I mean, Arshad and I can tell you, if I take one of my AMD patients or DME patients off of anti-VEGF for six months, really nine months, you know, they're gonna tank, the vast majority of them. The natural progression is not going to leave any room for improvement in these patients. But that's just phenomenological. How can you look at, you know, a disease-modifying effect here? Can you look at a tissue remodeling effect here? The group of us have talked about this a little bit. I think Jamie mentioned that we're going to look at ischemia in the diabetic macular edema patients. We can have very high resolution of the capillary blood vessel structure in the macula. In the next study, if we look at that either with fluorescein angiography or OCTA, with high resolution, we may see that there is some improvement in the blood supply in these patients with diabetic macular edema. If that's the case, I think that would be more concrete in showing this tissue remodeling effect. Jamie, maybe you want to talk about it. We're exploring some things that are, you know, even unfamiliar to me as a clinician, looking at FAF imaging of the macula. Again, ways to look at stressed cells in the retina. Jamie, do you wanna go into that? Yeah. I mean. This is all speculation we're talking about for the next study. Yeah. I think it's a great point. The only thing I'll add today is that we are deeply interested in biomarkers of mechanism engagement and how we might be able to monitor these patients. We do have some work going on in the biomarker arena. As that matures and we have some more confidence in some of those, we'll be sharing those externally. But we do have significant interest in understanding how we are actually impacting the retina in a positive way through a whole variety of modalities. Thanks, Jamie. Thank you for the questions, Brandon. Our next question comes from Salim Syed from Mizuho. Salim, you may go ahead and unmute your line. Great. Congrats on the data, guys. Just a few from me, if I can. For the KOLs on the line, Dr. Arshad Khanani and Dr. Robert Bhisitkul, I wanted to just get your view. Obviously, Dr. Arshad Khanani, you mentioned that reducing treatment burden is something that you find favorable here. On slide 25, I think there was, you know, a comparison showing the BCVA gain of 10 letters, 60% in patients for both the BCL-xL UBX1325 and also the VEGF. Just curious here, what else do you need to see here in order to gain confidence in this data set? How are you thinking about UBX1325 in the treatment paradigm ahead of VEGF, given you do have a treatment burden here, but obviously it's a newer therapy. Just curious, what else do you need to see here to get confidence in the drug and the data? A quick one on if you're assessing, for the Unity team, results post 24 weeks, given we still haven't seen any real decline in effect here at 24 weeks. Just lastly, a clarification for the Unity team here. Did the AMD trial get pushed out here for any particular reason? See, I think it was 4Q 2021 prior, now it's first half, and I think prior we were going to get data in the first half, and now we're getting the 12-week data in the second half. Just curious if there was a reason for the push out there. Thank you. Yeah. Thanks, Salim. Let me just kind of direct the question. Maybe for the first part, Bob and then Arshad, you guys can comment on the first part about, you know, what we're seeing in this and what more do we need to see in this upcoming studies to further increase our confidence of robustness of these data sets. And then I'll take the questions related to, you know, how we'll get to data beyond 24 weeks and the timing of the AMD studies. Bob, we'll start with you. Yes. You know, it's very interesting in this population, especially for patients who aren't responding well to anti-VEGF. There's an immediate indication once it's in my hands and I can use it in the clinic for, you know, that substantial proportion of patients that aren't completely resolving with Eylea or with Lucentis. These patients are ideal candidates to switch over to a different mechanism and a different treatment modality. More interesting to me, especially in the setting of diabetic macular edema is, you know, this is a single injection. You're not embarking on with your patient on these every month or every two-month injections for years and years. Is this something that I might use as an early intervention? You know, this is entirely speculative given the phase we're at here. If you gave me something that was disease modifying that sort of clears out the dead underbrush, so to speak, in the retinal tissue, it might be something that I use first before they require anti-VEGF. I'll turn it over to Arshad. No, I agree with you, Bob, and I think it's a really interesting question about what else we need to learn. Excuse me. The first thing is obviously is phase I'm looking at safety. I am very impressed with no DLTs, but we need to put it in more patients to confirm that. Obviously, I'm continuing to look for safety in the phase II trials. Then, as Bob said, this is after a single injection. I think the durability and efficacy we have seen is pretty phenomenal. We need to see what kind of patients actually get the maximum benefit from this. Looking at the baseline characteristics of patients, and then, as Bob said, early intervention, can we have this treatment available earlier? Can it be a treatment by itself if you're seeing the durable effect? Also in combination. I think we are still gonna continue to learn, but for me, the positive things are very good safety and the sustained durability. I mean, pretty impressive to see DME patients go six months and maintain their visual acuity in the high dose. I think we're going to continue to learn more biomarkers, more baseline characteristics, more imaging characteristics. I think at this point, I'm pretty positive that we have seen the signal of efficacy, which I personally wasn't expecting with a single injection. Thanks, Arshad. I'll take the other question, Salim, you asked. About, you know, how will we learn beyond 24 weeks? The phase I study was designed as a 24-week study, and we have the data from that study. In that particular patient cohort, we don't expect to generate more data because most of those patients are now off study. We are very interested, however, in looking at durability beyond six months. I think, you know, previously, Salim, we probably talked about the fact that this was kind of in our target product profile. If something gets to up to six months, that would be very exciting. All the feedback from the KOLs was that. The fact that we see sustained improvement through six months suggests that maybe these patients could go longer, right? We will learn that. I believe our first opportunity will be in a potential long-term follow-up to the phase II DME study. The current study is designed through 24 weeks, but we're having internal discussions about how we can follow those patients longer to see what the total durability might be. With regard to the timing of the AMD study, you will recall that previously we have shown a study design of a phase II-A followed by a phase II-B study before going to a pivotal study. There we had thought that maybe we'll start a phase II-A AMD study towards the end of this year, maybe a phase II-B study towards the end of next year, and then a pivotal, you know, a year and a half after that. As we have seen this data and have thought about study design, we see an opportunity to explore some of the regimen within this next AMD study that's coming up, and I don't want to get ahead of myself, but we will share details of that study in the upcoming months. We are going to explore whether we can introduce a second dose in that phase II study as well, so that we learn something about what we can get with a single dose as well, what we might get with two doses. That, we believe, could enable us to go from that phase II study to a pivotal study. This is important. If we were able to do that, we might be able to move up the pivotal study quite a bit and into 2023, which would be really exciting. Because of that, we're taking a little bit more time to kind of finalize the design of that AMD study, and that's the only change that has shifted the timeline a bit. Hopefully that gives you some context about the AMD study timing. Yeah, very clear. Thanks so much. All right. Congrats. Thank you for the question, Salim. Our next question comes from Matthew Harrison from Morgan Stanley. Matthew, you may go ahead and unmute your line. Great. Good morning. Thanks for taking the questions. I guess two for me. First, can you just talk more broadly about dose selection? I know you just touched on this a little bit, but I guess what I'm asking is, do you think you might use different doses with DME and AMD, or is it more about repeat dosing? Second, if you could just spend a few more minutes talking about the anatomic changes. I'm just wondering how important they are as you think about this data set, given the small number of patients versus the letter changes and how you think about sort of durability of the anatomic changes. Thanks. Thanks, Matt. I think we'll have Jamie take the first question that has to do with dose selection and using different doses versus repeat dose. And Bob, maybe you can comment a bit more about, you know, what do we learn when you have relatively few patients when we have anatomical data that you suggested the AMD patients and, what do we learn from those case studies, right? Jamie, do you want to start off with kind of, Yeah. the dose selection, changing dose versus frequency? Yeah. Matt, great question. Something that I think about regularly and all the time. Clearly we have only the initial assessment of dose range. As part of the additional studies beyond this, we'll be doing additional dose ranging. I think in what we're clearly seeing is that we're confirming some of the initial hypotheses we had in terms of the doses that would lead to greatest degrees of efficacy. We're pleased, very pleased to see the high dose patients achieving the kind of letter gains that we're achieving in the DME patients, and we're clearly seeing pharmacology in the AMD patients as well. Our future studies will definitely include additional doses just to make sure that the dose range we're using is appropriate for the different diseases. As I kind of pointed out, they'll each need work. Separately, and potentially in the same studies, we'll also be exploring some of the regimen data. As Anirvan alluded to, while we're still working on the final design of that study, and we'll share more in the future, it is our expectation that we'll be delivering at least a second dose to patients with AMD and exploring the impact that that may have. As we begin to learn what a second dose may deliver, especially in the AMD population, that will help us understand what the eventual optimized regimen will be for patients. What we're most pleased about is especially what we're seeing in the DME patients is there's this initiation regimen, which for the DME patients appears to be one dose, and we're hoping in the AMD side it may be two doses. Then there's a maintenance phase, and we see in the DME patients that's lasting a minimum of six months so far. Very reassuring for us and we have more work to do. Let me turn it to Bob Bhisitkul for the question in terms of the structural impact that we're seeing and what that tells us about UBX1325, especially in the context of seeing such a great functional outcome. Yeah. I mean, Matthew's question gets to the heart of what a phase I study is, which is a small number of patients. Okay? This is an open label study, and the FDA will not allow you to put more than, you know, 5 or 10 patients into a study group like this. So, you know, by its nature, we're dealing with very small ends here. Primarily the phase I study is for safety, of course. Then looking at the secondary endpoints, we get this happy surprise that we're seeing at least a signal of efficacy on the endpoints that I care about, which is, you know, visual acuity and changes on the OCT. There's high variability in all of these. If I just treat any single given patient in clinic, I expect things to take a different amount of time and a different degree of benefit from patient A compared to patient B. That's just the variability in the population, the biologic variability really. You know, I think some of that is compensated for by an effect that's big enough to be detected in the face of that background noise here in this phase I study, or at least that's one way to interpret it. Your question gets to the heart of what we really need to do, is we need to put, you know, 10, 20, 30 patients in each arm in the phase II study to get a better sense of what the size of the effect is and what the time course of the effect is. Thanks, Bob. Maybe I'll just add one more thing, Matthew. I think Bob pointed out that, you know, in some patients we do see improvement in CST and in others, we see kind of the stable maintenance of that CST. I just want to put that in context a little bit with something else that was pointed out about kind of what kind of CST changes require retreatment in these studies. In the phase II studies, typically there's a pretty well-defined criteria, which tends to be around 75 microns of CST gain. If you look at these data sets, you'll see that generally patients are not getting close to that criteria. I expect that at least for that reason, the changes are such that one should be able to go to significant durability before you need retreatment. As Bob pointed out, I think we really need more Ns, more patients to really see which of these changes are seen consistently as a drug effect and when do they show up. I mean, one of the interesting things that we've seen in some patients is this somewhat kind of longer term resolution, right? Which indicates that the tissue continues to remodel itself over time. It'll be interesting to see if that is seen in additional patients. Thank you for the questions, Matthew. Our next question comes from Ashiq Mubarack from Citigroup. Ashiq, you may now unmute your line. Hi, this is Ashiq on for Yigal Nochomovitz. Thanks for taking my question. I just wanted to ask about the sham-controlled phase II study. I realize sometimes the placebo response, especially on letters, can be somewhat strong in these studies. My question is about how you're thinking about control and powering in that phase II. Thanks. Thanks, Ashik. I think I'll direct this question to Jamie to speak to the design of the phase II study and how we're thinking about powering. We have taken that into account, Ashik. We know in general that there can be some variability in diabetes, especially related to glucose control. There is sometimes the possibility of some learning during BCVA ascertainment. I would just point out, we were very pleased to be able to provide today the fellow eye data in the DME study and DME patients, just to give an insight into the fact that we're at least in terms of the control of the study itself. It's not really a control for the letter game. For the study itself, there was minimal excursion of the BCVA in the fellow eye, suggesting that diabetes control or a learning effect did not impact greatly any of the changes that we're seeing in the treated eye. In fact, the kind of letter gains we're seeing, the excursions we're seeing in that fellow eye of 1-2 letters is kind of what you might be able to see in a study. We've taken all that into account as far as the powering in the phase II study with the sham control. We are confident that the results that we'll see looking at change from baseline and compared to the sham patients will give us great insight into the efficacy of UBX1325 in that population. Ashiq, just to be specific, we have around 60 patients planned for this. Yes. This phase II study that we're designing about 30 sham, 30 active, and we believe that will give us sufficient power. Okay, great. Thank you very much. Thank you for the question, Ashiq. This concludes the verbal portion of our question and answer session. I'll now turn the call back over to Lynne. Thanks, Tara. I'm gonna give it back to Anirvan for closing remarks, but I did want to thank everybody for joining the call. If anybody has further follow-up questions, they can certainly send me an email. Thanks very much. Anirvan? Yeah. Thanks. Thanks, Lynne. Thanks everyone again for joining this call. As you can see, you know, pretty exciting data, although an early-stage study, not powered for any kind of efficacy, but to see this early signals of efficacy is really encouraging. Thanks, Arshad again for providing context about what the current therapies demand of patients and Bob for kind of sharing the data that we have so far. We will continue to provide updates as we generate data. For us, this is an important point in our study. We've just completed that first phase I SAD study. Also Jamie and the internal team for delivering, I think, a really robust study that we can base our future studies on. Thank you again for everyone for joining, and look forward to providing future updates.