Good day, and thank you for standing by. Welcome to the Unity Biotechnology KOL Conference Call. At this time, all participants are in a listen-only mode. After the speaker's presentation, there will be a question and answer session. To ask a question during the session, you will need to press star one on your telephone. Please be advised that today's conference is being recorded. If you require any further assistance, please press star zero. I would now like to hand the conference over to your speaker today, Lynne Sullivan, Chief Financial Officer. Please go ahead. Good morning. Thank you for joining Unity Biotechnology's conference call this morning to discuss the phase I results from our UBX1325 program. With me on today's call is Robert Bhisitkul, Professor of Ophthalmology and Director of the Retina Fellowship at University of California, San Francisco, a renowned retinal specialist. Anirvan Ghosh, the CEO of Unity Biotechnology. Jamie Dananberg, the Chief Medical Officer of Unity Biotechnology, and myself, Lynne Sullivan, the Chief Financial Officer. 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. We do not assume any obligation or intent to update them except as required by law. With that, I'll hand the call over to Anirvan to start the discussion. Thank you, Lynne. Good morning to all those joining us on the call today. I'm really pleased that we have the opportunity to review data from the phase I single ascending dose study of UBX1325 in patients with advanced diabetic macular edema and age-related macular degeneration. As you know, these are devastating diseases that rob patients of their vision and independence. While anti-VEGF therapies have been the standard of care for about 15 years, they pose significant patient burden. Many patients do not respond optimally to these treatments. We have Bob Bhisitkul from UCSF with us today, who has had the opportunity to review the phase I data in detail. He will share his perspective on the data on the call today. Since some of you may be new to Unity, I'll start with a brief background on Unity and the senescence disease hypothesis and then hand it to Robert Bhisitkul to go over the data. On slide four, at Unity, we're focused on developing transformative medicines to slow, halt, or reverse diseases of aging. The primary areas we're focused on are in ophthalmology and in neurology, and the primary biology we're targeting is cellular senescence. I'm going to go through briefly what senescent cells are, why we believe they contribute to disease progression, and how we are attempting to target that biology to lead to improved patient outcomes. In slide 5, we see from left to right the progression of disease, and illustrated on this slide is the fact that in the course of aging, there's an accumulation of cells that are dysfunctional, often under stressed conditions. These cells stop dividing and then secrete factors that can be damaging to the local microenvironment. These cells are called senescent cells, and we have generated extensive preclinical data that indicate that if you are able to eliminate senescent cells, you can alter the trajectory of the pathophysiology that characterizes the disease. With that in mind, we've been developing senolytic medicines that can target those cells. The first disease where we have been examining the role of senescent cells in vascular biology is in the eye. On this slide, we illustrate that we know that in the context of diseases of the eye, like AMD and DME, there is an accumulation of fluid within the retina that accompanies loss of vision and great disability. We believe that as the disease progresses, there's an accumulation of senescent cells in the blood vessels indicated in the lower part of the slide, and those senescent cells can secrete factors that lead to an inflammatory environment in the eye and can also lead to vascular leak. Our goal is to develop agents that will remove those senescent cells and restore the blood vessels to a healthier state and change the course of disease progression. This slide indicates where our leak molecule, UBX1325, acts in the cascade that we believe leads to disease progression. In the context of diabetic eye disease, the cellular stresses that the eye and the vasculature face leads to accumulation of senescent cells in blood vessels, which in turn leads to accumulation of a number of inflammatory factors shown on the lower part of the slide. You're all familiar with drugs that target VEGF, which is one of those factors, and anti-VEGF factors have provided considerable benefit in patients with DME and AMD. With UBX1325, we are targeting a node that is upstream of these factors, and we believe that this could lead to greater benefit and greater durability of effect. The next slide provides an overview of the key features of the phase I data. UBX1325 is the first senolytic agent to be taken into eye disease, and we find that it has a favorable safety and tolerability profile. Initial review of the data indicates that it leads to a rapid improvement in vision in a number of patients, as well as improvements in retinal structure that are believed to be associated with disease progression. It is a mechanism that is distinct from anti-VEGF, and therefore we believe that it could work together with anti-VEGF or as a monotherapy. By reversing the pathophysiology of disease, it could lead to a disease-modifying treatment option. It's also important to note that senescent cells are found in a number of other diseases, a number of other indications. The data set that we have generated supports the ability of targeting senescent cells to lead to improved outcomes, and we're excited to explore the impacts of this approach in other diseases as well. The next slide gives an overview of the clinical development plan. Today, we'll be talking about the phase I data set from UBX1325. This study is ongoing, but we have completed the single ascending dose phase. It is in fairly advanced patients, and in a few minutes, Robert Bhisitkul will share some of the key observations from those patients. Based on what we saw in the initial patients, we were quite encouraged by the data we saw in the AMD patients and are enrolling additional AMD patients in that phase I study and expect to have a full readout of that AMD data set, the eight-week data, towards the end of this year. We've also recently initiated the phase II-A DME study. That study is a sham-controlled study following a single dose of UBX1325, and we expect to share data from that study in the first half of 2022. Finally, we are exploring the possibility of initiating a parallel phase II-A neovascular AMD study that could potentially start in the second half of this year and generate top-line data in the first half of 2022. With that, I'll hand it to Bob to go over some of the data from the phase I study. Thanks, Anirvan, and thanks very much for the chance to discuss the clinical program for this compound, UBX1325, today. I'll be talking about the phase I first-in-human study with this compound. Of course, these studies are primarily to determine the safety of UBX1325 as a single intravitreal injection. They also give us an opportunity in this small number of patients across a number of doses and, of course, across two diseases, diabetic macular edema and wet macular degeneration. They give us an opportunity to do some exploratory observations on biological effect in terms of vision and in terms of anatomy that we can see on the OCT. Here's the structure of the phase I study. This is a single intravitreal injection, and starting at the lowest dose at 0.5 mcg, and then ascending through three higher doses, and at the highest dose of 10 mcg with three patients in each cohort. As I said, the study population is patients with advanced diabetic macular edema and wet macular degeneration. It was required that these patients be determined by their treating physician, by the principal investigator in the study, to be not receiving any further benefit from anti-VEGF therapy, the standard of care for both of these diseases. Either incomplete responders or non-responders. For the design of the study, I think we can keep in mind that there was a washout period of three months. That is, the patients could have no anti-VEGF therapy for three months prior to entering into this study. We had the usual inclusion criteria in terms of OCT and anatomy for the patients with diabetic macular edema, as well as for macular degeneration. Here is just the top-line results, and this is an early readout from this study, which is still ongoing. First and foremost, in terms of safety and ocular tolerability, this drug has a good safety profile. These patients had no sign of any dose-limiting toxicities at the highest dose, 10 mcg, and there were no adverse events or serious adverse events that were attributable to the drug itself. In terms of vision, overall, there were some signals of a benefit for this drug in this small number of patients. At two weeks, 10 of the 12 patients showed a gain in vision from their baseline. At four weeks, this was nine out of the 12 patients. When we look at the higher dose cohorts, the 5 mcg and the 10 mcg doses, six out of six patients showed vision gain from baseline at two weeks, and five out of these six patients showed vision gain at four weeks. Looking at the OCT and the central subfield thickness, this was decreased from the baseline, which we consider a positive benefit for patients when we're treating them to see a decrease in the thickness of the retina. Overall, for all the doses, six of the 12 patients had a decrease at 12 weeks, five of the 12 patients had a decrease at four weeks. Then again, when we look at those two higher dose cohorts, four out of these six patients showed a decrease at two weeks, and three out of these six patients showed a decrease in the OCT at four weeks. We see a reduction in the subretinal and intraretinal fluid in the wet macular degeneration patients. Taken together, the clinical impression here is that this is a strong signal that we have disease-relevant biologic activity. Again, in this phase I study, we'll first look at the safety results here, and as you can see from this table, very favorable safety events with none of the warning signs that we look for in a safety study. In particular, there were no episodes of intraocular inflammation that were observed. There were two events with vision changes in patients that were not deemed related to the drug, and also two patients that had subjective symptoms, again, not attributable to the drug itself. As far as the other toxicities and adverse events that we look for in terms of retinal detachment, in terms of ocular infection, retinal hemorrhages, there were none of these observed. Overall, again, we have a very good safety profile. Taken together, this is a strong support to proceed to subsequent clinical development of this compound as an intravitreal injection in further studies. Now we'll turn to looking at the biological activity of this drug. With this phase I data, we have an opportunity to do an exploratory evaluation of some of the early readout from the patients with macular degeneration and diabetic macular edema. This first slide is showing just the two highest dose cohorts, the 5 mcg and the 10 mcg doses of UBX1325. Just to explain the slide a little bit, you can see that the doses are distinguished by color, the purple versus the orange, and the patients with wet macular degeneration are shown by the dotted lines, and those with diabetic macular edema are shown by the solid lines. Then just as reference, you can see that there is the red Xs, which is a cross-trial comparison to the expected effect that would've been seen with treatment and with using of aflibercept as extrapolated from the VISTA phase III clinical trial. My takeaway from this slide in these two dose cohorts is that the majority of the patients show improvement in their best-corrected visual acuity from their baseline vision that is present at four weeks and even extending out to eight weeks, at least to some degree in these patients. There's one exception of a patient who doesn't show any benefit from this disease. We, as a safety assessment committee, we spent some time looking particularly at this patient, who was quite advanced macular degeneration with some complexity to the disease. The decline in the vision in this patient was thought to be related to disease progression and not something that was attributable to the drug UBX1325 itself. Excepting that patient, we see that there was, overall in this group, a very encouraging signal in terms of biological activity that we can see from functional improvement as measured by visual acuity. At the same time, we'll look at the OCT results. This is looking at the retinal anatomy and the reduction in fluid and edema and thickness that we can see on the OCT. Again, here, looking at only the two highest dose cohorts, we can see that, in this case, going below the dotted line is a sign of a biologic effect and a sign of improvement in the retinal thickness. We can see that both for the macular degeneration patients and for the diabetic macular edema patients, there were subjects who showed a good improvement in their OCT that was evident at two weeks, four weeks, and in some cases even sustained to some degree, at least, out to eight weeks. Now, as retina specialists, what we really like to do is look at individual cases of these patients and to look at the OCTs. I've had a chance to do this with Jamie and the team for all of the patients in the group. We've selected two patients from each of the disease categories, two from diabetic macular edema and two from wet macular degeneration. I think it'll be interesting to go through each of these cases one by one. This is the first case that we'll talk about. This is a patient with diabetic macular edema and at the five microgram dose. You can see, again, one aspect of this study. It's the first in human studies, so our investigators are picking out patients who have advanced disease. I can tell you from clinical experience, this is a very advanced case of diabetic macular edema. You can see it in those large cysts shown as black round spaces within the retina, severe thickening, and particularly that very large cyst right at the center of the macula we see as severe and chronic diabetic macular edema. You can see in this patient, after a single injection of UBX1325, there's reduction in that cystoid macular edema that we see there. The large cyst is cut in the size by about a half, and we also see the other cysts and the diffuse edema is also improved. That can just be seen in the graphs below in terms of the central subfield thickness being improved at 4 weeks for a substantial lowering. You can see that this is also correlated as we like to see. It doesn't always happen, but in this patient's case, it's correlated that the improvement on the OCT is also correlated to an improvement in the visual acuity compared to baseline. We have a second patient here with diabetic macular edema, again in the 5 mcg dose. Here you can see at baseline, again, severe diffuse macular edema with large cysts denoting chronicity. At week four, after a single dose of UBX1325, we can see there's persistent diabetic macular edema, but we have a perceptible improvement in the OCT that we can see here. Again, that improvement that's seen in terms of the central subfield thickness is correlated to some improvement that we see in the visual acuity in this patient as well. In two advanced cases of diabetic macular edema, the OCT is giving us a signal that there's a biological effect with this, and that's correlated to a functional improvement in terms of the vision. Now we'll switch to patients with wet macular degeneration. This is showing a patient at the one microgram dose, the low dose. One of the hallmarks of wet AMD is the subretinal fluid. You can see that here at the baseline, that small pocket of black space, that's the fluid denoted by the white arrow there. Very typical for wet macular degeneration, particularly can be seen in a chronic situation. We can see something that is, to me, quite striking here for a patient with wet AMD is that at week eight, after a single dose of UBX1325, we see resolution of that subretinal fluid. As a clinician, this is not natural course of this disease, and it's giving us a signal that there's some biologic activity associated with this treatment. Again, pointing out that these are patients that for at least three months have had no anti-VEGF therapy on board as well. It's nice to see that this anatomic improvement that we see on OCT is correlated with an improvement in vision from baseline in this patient. For our final case, we'll show one more case of wet macular degeneration. This is a case at the five microgram dose. Again, at baseline, you can see not only the white scar, the white fibrosis, sometimes we call this SHRM, on the OCT, but overlying that is a pocket of subretinal fluid. You can see those irregular black shapes. If you squint, you can see that there's also, on the left-hand slope of this scar, a little bit of subretinal fluid overlying the scar, which is again, very typical of wet macular degeneration. Here at week four, after UBX1325 treatment, we see improvement in that subretinal fluid. Okay. The black cysts on the right side of the scar are reduced and the overlying fluid on the left side, left slope of the scar, is completely resolved in this. Of course, I'm just showing you one cut through the OCT. with the team, we've been able to verify this by looking through the entire slab or all the cuts for the OCT to see this improvement and resolution of the subretinal fluid. Again, it's nice to see that we see that reduction in the central subfield thickness on the OCT, and that correlates nicely with the improvement in the best-corrected visual acuity in this patient as well, going all the way out to eight weeks. again, just as a summary, from the phase I first-in-human study of UBX1325, we see a favorable safety profile. We don't see any dose-limiting toxicities, even at the tight 10 mcg dose, and we don't see any drug-related adverse events. In particular, we didn't see any intraocular inflammation with intravitreal injection of this drug. On the exploratory study, to look at some of the data from the early readout, we see some positive signs in both vision where 10 out of 12 patients showed a gain at two weeks, nine out of 12 patients shown a gain at four weeks. When we concentrate on just those higher dose cohorts, we see six of the six patients showing a gain at two weeks and five of these six patients showing a gain at four weeks. Overall, a strong signal in visual benefit from this that is worth pursuing in further clinical studies. In correlation with this, we can look at the OCT and the central subfield thickness, and here again, a large portion of the patients showed improvement in the OCT across all doses. When we look at the higher doses, four out of six patients showed a decrease in the OCT thickness at two weeks, and three out of the six patients showed an improvement at four weeks. Again, I'll point out that these are patients with advanced disease who have been chosen for this first-in-human study. All the more striking to me that we're seeing some signals both in terms of vision and in terms of OCT with these patients. Again, my clinical impression, as a retina specialist treating patients and also having looked at previous clinical trials, is this data overall gives a strong signal that we have disease-relevant biologic activity with intravitreal UBX1325. Thanks. With that, I will turn it over now to Jamie. Thanks, Bob. This is Jamie Dananberg, the Chief Medical Officer at Unity. I really appreciate Bob's review of the data from our phase I study to date. It is that very data that supported our decision to proceed to a phase II-A proof-of-concept study in patients with diabetic macular edema. I'd like to share some of the design elements of that study and what it is we're exploring from that study as we move forward. These are patients with diabetic macular edema who are currently receiving anti-VEGF therapy and have had at least three consecutive anti-VEGF treatments, but still have residual structural edema with a CST of at least 350 microns. Basically, the design of the study is that patients will have been receiving their typical anti-VEGF regimen of once-a-month injections. At the time of a consecutive injection, they will receive either UBX1325 or sham, and then we'll continue to follow these patients for a period of up to 24 weeks. That allows us to explore a number of elements for these patients to help us understand the activity of UBX1325 in a set of patients who are much earlier in disease than what we saw in the phase I study, and for whom we believe UBX1325 could represent an important therapeutic option. On the next slide, we describe what some of those endpoints are that we're exploring. Of course, we continue to evaluate the safety and tolerability of any intravitreal product in diabetic eye diseases. Of course, we're interested in the functional improvement that we might be able to observe, which is assessed by BCVA, and also the correlative structural changes that we are deeply interested in, particularly in central subfield thickness in a disease like DME. We're also looking for changes relative to diabetic retinopathy, and for that, we'll be using fundus photography and assessment of DRSS scoring. We're also looking at the ability to no longer have these patients require ongoing anti-VEGF therapy. Many of these patients who come into this study would require anti-VEGFs monthly for up to a period of almost two years in order to continue to gain benefit. It is our hypothesis that should UBX1325 demonstrate the type of efficacy that we've seen in the phase I study, that we should be able to significantly or completely diminish the need for additional anti-VEGF therapy. Of course, we're also looking for other benefits that might be important in a disease like diabetes, where we know ischemic regions and poor flow are important components of that disease and probably drive VEGF production. We're also using measures like OCT angiography and wide-field angiography to understand capillary non-perfusion and potential reperfusion of zones that had been previously ischemic or non-perfused. With that, I just want to summarize therefore what we think the overall transformative nature of UBX1325 could represent for patients with diabetic macular edema, and frankly, also with patients with wet AMD. We believe we could have a rapid effect with greater efficacy and durability than what they're currently receiving in standard of care. That is one or maybe several injections of UBX1325 would lead to full response, followed by a period of many months where patients would not need additional therapy. We believe what's important is that this is a novel mechanism of action and a favorable pharmacology and safety profile, which means that the drug could be used as first-line agent. It could also be used in combination with anti-VEGF treatments. Finally, it could also be used in patients for whom anti-VEGF agents have failed to demonstrate ongoing efficacy. We believe it could have unique properties, such as improvement in retinal or choroidal blood flow in these patients, which could strongly change the trajectory of these diseases and basically making this a true disease-modifying agent, the first one for these kinds of diseases. For us, this represents a unique and extremely important opportunity that could greatly impact the trajectory that patients experience with these diseases. With that final comment, I'll turn it back to Anirvan Ghosh, and we can open it up to questions. Anirvan Ghosh? Thank you, Jamie. Thank you, Bob, for sharing your perspective on the initial data from this phase I study and noting the significance of the favorable safety profile and the structural improvements seen with UBX1325 in both DME and AMD patients. Thank you for the time you took to go through the data carefully, which has informed our view of the data. Also, thanks, Jamie, for reviewing the design of the phase II-A study, which we recently initiated. As highlighted by Bob, these are compelling findings for a phase I safety study that was not designed or powered to detect an efficacy signal. We are enthusiastic about the initial data we've seen with UBX1325 and find the improvements in vision and CST highly encouraging. It's worth noting that this is a safety and tolerability study in fairly advanced patients who are not expected to benefit from further anti-VEGF treatments. To see an effect in patients who are not responding well to standard of care is really quite exciting, and we find this opportunity to explore a new therapeutic hypothesis compelling. As noted, we have initiated our phase II study in DME patients and look forward to sharing that data in the first half of 2022. As I mentioned, we are also enrolling additional AMD patients in the phase I study and expect to share phase III data from the AMD patients later this year. We're excited about the progress of the studies, both the phase I study and the phase II study, and look forward to updating you in the coming months. With that, we would be happy to take questions. Thank you. Ladies and gentlemen, if you'd like to ask a question, please press star then one on your touchtone telephone. Again, to ask a question, please press star then one. One moment for our first question. Our first question comes from Salim Syed of Mizuho. Your line is open. Great. Good morning, and thanks for all the color to the team and to Bob as well. Bob, I had a couple of questions for you. we talked about on this call that these are advanced patients. Just curious if you would've initially expected to see any efficacy in these patients whatsoever, and then how do you reconcile the fact that we aren't really seeing any dose response here given it's really the five microgram dose where you get up to those 50% BCL-xL inhibition levels. How do you reconcile the fact that we're seeing responses even at the lower doses given, I think it was 10 out of 12 patients total getting efficacy. the second question here is, in terms of treatment paradigm, just given the data to date, just curious how you're thinking about where do you see UBX1325 fit into treatment paradigm. Would you use it as a first-line agent, second line combo, in both the DME and AMD settings? Thanks so much. Okay. Great questions, and let me take your third question first, which is how will we use this? Will it be a first-line treatment? Will it be a combination therapy? Will it be a monotherapy treatment? We're very early, but my instinct as a clinician is the answer is yes to all of them. In terms of combination therapy, I think the retina community wants to have combination therapies. Right now, we're really a monotherapy. We've got one tool, which is the anti-VEGF, and we've been looking for five or 10 years for something that we can add to that very powerful drug, in order to get additive or synergistic effects. I think that we will consider it both as an adjuvant therapy and also as a monotherapy. As monotherapy, I think we'll look at it either for that, what you want to call it, 30% of patients who are poor responders to anti-VEGF. We'll either look at it for those or from the mechanisms of this drug. Remember, it's not acting against a factor. It's really acting on the tissue of the site of the disease, which is the pathologic blood vessel. What we're really doing here is altering the tissue. We're altering the cellular makeup of the blood vessel. there's a strong, at least conceptual argument to use it as a first-line therapy in that case, and possibly as an early intervention therapy for, say, patients who are beginning to show signs of diabetic retinopathy to prevent them from going on to lose vision from the more advanced stages of the disease. We're very early here, but as I just speculate and envision how it'll be used, I think it'll be at least investigated in all of those different ways to use it. I hope that through the clinical development program, we also look at different arms that can look at these different scenarios as well. Your first question was about advanced disease, and I think that's just natural for a first-in-human study. We're injecting a new drug into the eyeball. I think the principal investigators are going to pick their most severe cases, sort of maybe where you've already proven to yourself that they're not going to respond to the one tool that we have, anti-VEGF, and somewhat you're in the category of nothing to lose with these really severe cases. Two things that surprise me is those tend to be the most stubborn cases, the really advanced cases of either DME or macular degeneration. We're seeing at least a signal of an effect clinically with these patients. The second part of it is, remember, they're washed out for three months. They haven't had any anti-VEGF on board for three months before the study starts. We go out to eight weeks. Okay, an additional two months. We've got five months with no standard of care on board. Again, to me, all the more meaningful that we can see any responses there. Your second question was on dose response, and it's a 12-patient study. Our N is very low here. In any of these studies, really what we're looking for is safety, of course, and then everything else is exploratory in terms of looking at effects. There's no chance of seeing a positive P value and statistical significance with 12 patients, four different doses. There's no chance, really, of structuring a good dose response curve here. Particularly, remember, some of the higher doses have not even completed the study yet. They're still ongoing. The low dose, the 0.5 mcg dose, and the 1 mcg dose showing some effect, I think it's optimistic that we see an effect even at these low doses. The optimal therapeutic dose in the eye is not determined for this. Again, it's nothing that we could construct a dose response curve on. The fact that they saw safety at the highest dose, 10 mcg, to me, I've been encouraged that that's the dose to go forward with, because we don't see any dose-limiting toxicities. Does that address the questions? That's super helpful. Thanks so much. Okay. Thank you. Our next question comes from Yigal Nochomovitz of Citi. Your line is open. Hi, this is Carly on for Yigal. Thanks for taking our questions. Dr. Bhisitkul, thanks very much for the detailed presentation. Can you share your thoughts on the underlying therapeutic hypothesis that Unity is testing of targeting senescent cells in the retina? And then secondly, how important is it, in your view, to see biomarker data from patients showing that UBX1325 is in fact reducing the senescent cell burden in the retina? As you may know, Unity has shown this pre-clinically, but just curious whether this is something you would like to see in patients in order to establish proof of mechanism and help validate some of the efficacy signals observed. Thanks. Yes. Your second question first. This is novel. Okay? This is not only a novel disease target, but it's almost a novel therapeutic concept that we're not blocking an individual factor here. We're actually altering the tissue population, the cellular population of the tissues. In animals, you can show it. Unity has good markers to show senescent cells, and they've got very convincing data in their animal models. In humans, of course, we can't take out the eyeballs and do histology and do staining of the tissue. One of the things that we're talking about with the group is looking at secondary markers that could show some restoration of the tissue. For example, for the endothelial tissue, you could look at a sick capillary in the retina will have poor blood flow. If you can eliminate those sick cells on the endothelium and the vascular pericyte cells, and you can repopulate them with healthy ones, you may see some restored blood flow, reperfusion. That's something that we can look at now with some of the new modalities that we have, both OCT angiography as well as wide field fluorescein angiography. With diabetic patients, we know areas of non-perfused retina are one of the hallmarks and one of the problems. It's going to be, as Jamie pointed out in his presentation, to look for restoration of blood flow is going to be one of the secondary endpoints that we'll look at in the phase II trials and further on. I think that would be a good marker that you've actually changed the cellular population of the target cells in the blood vessels. Other than that, it's not as simple as just taking ocular fluid samples to look for, say, anti-VEGF levels or things that we already do when we treat with the anti-VEGF drugs in the clinical trials. Because this is a more, what do you want to say, broad spectrum therapy, we're hopefully going to be suppressing a whole host of these cytokines that are involved in the disease. you see the difficulties with looking at cellular populations in a living human eye. your first question, I'm sorry, Carly, what was the question again? Yeah, the first question was just more broadly your thoughts on the hypothesis here of targeting senescent cells. Oh, yeah. I think I addressed it. It's a totally novel concept, because we're talking about acting at the cell level, not at the soluble cytokine level. I've noticed even when we have calls with KOLs, it takes some time before even an experienced retina doctor can change from the mindset of, I'll stick in an antibody that neutralizes a specific factor. That's the mindset that we're in. Okay? Here what we're doing is we're actually, the concept is to repopulate the cells. Maybe it's almost turning back the clock on the tissue for some of these diseased blood vessels. The pacing of this and the long-term effects should be different. If we can really do this, it's not a one or two-month effect while you have anti-VEGF drug on board. It might be something that has a more sustained effect because you have, as I said, turned back the clock and removed some or renovated some of the diseased blood vessels and diseased tissues in the eye. Great. That's super helpful. Thank you so much. Thanks, Carly. Thank you. Our next question comes from Matthew Harrison of Morgan Stanley your line is open. Hi, this is Kostas for Matthew. One question from us. What, in your view, would the impact of the observed OCT changes expected to be on the clinical outcomes? Thank you. Yeah, that's always the factor. OCT is such a powerful thing for us retina specialists to look at to see effect because we're looking at anatomy almost at the histological level, at the micron scale level or a few microns of resolution. And this is well established, what you would expect is OCT gets better and vision gets better. Those two don't always go together. That's why Wiley Chambers and the folks at the FDA have really not adapted improvements in OCT as an approvable endpoint for anything that's being developed in retina. We definitely see OCT improvements as a positive sign. Sometimes it's the first thing that we look at, but we know to expect that that's not necessarily, in an individual patient, going to have a linear correlation with the vision improvement. We have to look at average vision improvements, and really what we're most interested in these days is the mean change in vision compared to baseline. That's going to be the ultimate factor. particularly in the early clinical trials, in phase I and phase II, you can get so much from the OCT data. Does that get to your question of the correlation between vision and OCT? It does. Thank you. Okay. Thank you. Again, if you'd like to ask a question, please press star, then one. Our next question comes from Salveen Richter of Goldman Sachs. Your line is open. Hi. Thank you so much for taking our question. This is Sonia on for Salveen. Doctor, in your view, what is the clinical bar for the upcoming eight-week AMD data and also for the phase II-A DME data in the first half of 2022, particularly since the phase II-A will evaluate earlier-stage patients? Yeah. What's the bar? It's still a phase II study. It's still an early study, but here we're going to have higher numbers. We're going to be using a more uniform dosing schedule, and we're going to, hopefully they're going to be able to recruit patients that are more representative of the patients that I see in clinic. They're not going to just be the very advanced patients, but they're going to be more routine patients with DME and macular degeneration. much more closer to the real world that we're in when we're treating patients. It's still a phase II study, so I've been in this with many other programs. Yes, you would love to see a + P value, okay, for the phase II study. I think I'm going to be looking for any strong trend, any believable trend from the treatment. If it reaches statistical significance, that's a home run in a phase II. That's really something that I require of a phase III more than phase II. The last part of that is, remember, these diseases for natural course, they don't get better. If I leave a macular degeneration patient untreated, no anti-VEGF on board, the natural course of that disease will not have variability that trends to some patients getting better on their own. It's really just not a feature of macular degeneration. I'd say the same for diabetic macular edema, with perhaps a little more up and downs in DME because some of that's related to their systemic blood sugar control and things such as that. In general, these are diseases that are sort of inexorably either persistent or progressive. Anything that you can see that's bending the curve, even if it doesn't reach statistical significance for either vision or for OCT central subfield thickness or other measures that we have on OCT, either of those would be very encouraging to me. Of course, seeing both of them would be very encouraging. Thank you. Our next question comes from Brandon Folkes from Cantor Fitzgerald. Your Your line is open. Hi. Thanks for taking the questions and for the presentation today. Maybe, Doctor, just following on from some earlier questions. Do you believe the senescent cell hypothesis initially may be best suited to any subset of your patients? Do you expect, should the company be successful, to use this broadly? Do you think you'll get, just given again that this is a very novel approach, do you expect to get the answers the community will be looking for through the clinical development process, or do you think there may be an element that is looking for real-world experience on the senescent cell hypothesis? That's a very interesting question, and maybe one that should be thought about for phase III. Is there going to be a subset of patients? Let's start with DME. Is there going to be a subset of patients that are more demonstrably related to senescent cells in the endothelium and the pericytes? I don't know if that's going to be possible. It's certainly something worth thinking about. In some ways, once you've reached DME, in this hypothesis at least. I'll even back up. Once you've reached diabetic retinopathy with the formation of retinal hemorrhages, with the formation of microaneurysms off of the capillaries, that, in this theory, is going to be indication that you have sick endothelium, and there's no secret about that. We know that the initiating factor in diabetic retinopathy is loss of the vascular pericytes, and that's secondary to the endothelium, and we know the endothelium is also sick in these patients. I don't know if we'll be able to determine a subset of patients that would be more responsive to anti-senescence therapy. I think we can say that almost by definition, the disease is, by the time you have appearance of diabetic retinopathy, you are in the senescent cell stage. Ideally, we'd be able to get histology and see those cells in the retina and see that reverse, but of course, in a human, that's impossible. Everything I've said about DME, I would also say about neovascular AMD. By the time you've started sprouting those angiogenic vessels from the choroid breaking into the subretinal space and sub-RPE space, you're in the senescent stage of this disease. You have sick choroidal endothelial cells. You've got sick retina RPE that is hypoxic and inflammatory, and by this hypothesis of senescent cells, that's directly associated or even attributable to endothelial cells being sick in the choroid in the case of macular degeneration. Great. Thank you. Thank you. It's something worth thinking about. Can we use some of our studies, probably fluorescein angiogram or OCTA, can we use some of those studies to identify a more susceptible population? It's something worth thinking about. Maybe just actually a follow-up there. When patients are presenting now in terms of deciding on what clinical trial to recommend them to go into, it sounds like you're open to recommending most patients to go into the UBX1325 trial. Is that correct? I think that's correct. There's not any patients you're not thinking about steering towards Unity's product at this stage. Yeah, I think that's correct. We see good safety, so I don't have any qualms about putting a patient in the clinical trial in terms of safety. Maybe the one patient that I have thoughts about just keeping it standard of care are the patients who are doing beautifully with aflibercept. Maybe those are the ones that I'll be unwilling to, first of all, wash out the aflibercept for months and then start them on a new drug. By the design of the phase II study, those patients, it's an inclusion criteria that the patients have to have had three previous anti-VEGF treatments with inadequate response and recurrent disease or persistent disease. That's not really a factor. As far as patients that I wouldn't allow into the study, with good safety and non-responsiveness to the standard of care, I think most PIs will be open to entering the patients in this study, particularly since it's a single dose. Okay. That's very helpful. I appreciate all the color. Thanks. Thank you. I'm showing no further questions at this time. I could turn the call back over to Anirvan Ghosh, CEO, for any closing remarks. Thank you. First of all, thank you, Bob, again, for joining us on this call and taking all the questions. Your views, and you've been on some of the other KOL calls, have significantly influenced our plans for the clinical development plan, as well as our assessment of the initial safety and efficacy data. Thanks for taking the time in all of those meetings as well as today. Also, for those people who are on the call today, excellent questions, and I hope you found the interaction with Bob engaging and helpful. I'll just close by reminding you that we have two ongoing studies now. In the phase I study, we continue to follow the existing patients, and we are enrolling additional AMD patients to inform a decision as to whether we would run a parallel phase II-A AMD study. We expect to have that phase I full AMD data set before the end of the year. We're also in the middle of the phase II-A DME study, which is enrolling, and we expect to share data from that study in the first half of next year. As Bob pointed out, it's an opportunity for us to learn about the safety and efficacy of UBX1325 in a broader, more typical patient population. The fact that we see early signals in very advanced patients makes us optimistic, and I look forward to keeping you all posted as these studies progress. Thank you all again for joining. Thank you. Ladies and gentlemen, this does conclude today's conference. Thank you all for participating. You may all disconnect. Have a great day.